Bisaryl compound and medicament for cancer treatment comprising the same

ABSTRACT

A medicament for treatment of cancer comprising a compound represented by the following general formula (I) or a physiologically acceptable salt thereof:  
     Ar 1 —S—R 1 —S—Ar 2    
     wherein R 1  represents a nonmetal bridging group; Ar 1  and Ar 2  independently represent a group selected from the group consisting of an aryl group which has, on its ring, one to three hydroxyl groups optionally substituted with a monovalent group and said aryl group may have one to three substituents other than hydroxyl group on its ring; and a heteroaryl group which has, on its ring, one to three hydroxyl groups optionally substituted with a monovalent group, and said heteroaryl group may have one to three substituents other than hydroxyl group on its ring.

TECHNICAL FIELD

[0001] The present invention relates to a novel bisaryl compound and amedicament for treatment of cancer which comprises said compound or aknown bisaryl compound as an active ingredient.

BACKGROUND ART

[0002] In the cell proliferation process, DNA replication process isregulated by a family of enzymes relating to nucleic acid synthesis.Among these enzymes, it has been reported that ribonucleotide reductase(occasionally referred to as “RNR” hereinafter in this specification) isa particularly important enzyme involved in the biosynthesis of dNTPs,which are precursors of DNA (Ann. Rev. Biochem, 57, pp.349-374).

[0003] In cancer cells, endless cell proliferation continues due toover-expression of certain families of enzymes and the like, which leadsto death of the host. It has been reported that RNR is over-expressed incancer cells to maintain high ability of cell proliferation of cancercells (Cancer Research, 43, pp.3466-3492). Moreover, there has also beenreported a possibility that malignant alteration of cancer is causedwith accompanying expression of RNR (Proc. Natl. Acad. Sci. USA, 93,pp.14036-14040). Therefore, an agent selectively inhibiting RNR isexpected to be able to exert highly selective toxicity to cancer cells,and accordingly, expected to be useful as a medicament for cancertreatment that selectively inhibits the proliferation of cancer cells.

[0004] Hydroxyurea has been known as a compound exhibiting antitumoractivity by inhibiting RNR, and the compound is used clinically as ananti-leukemia agent. However, the drug only has weak inhibitoryactivity, and therefore a high blood concentration need to be maintainedfor a long period of time to successfully inhibit RNR. In addition, thedrug causes strong side effects such as bone marrow toxicity, and henceis not a satisfactory therapeutic agent. For these reasons, it has beendesired to develop an RNR inhibitor which has potent RNR inhibitoryactivity as well as reduced side effects including bone marrow toxicity,and has a wide range of effective dosage.

[0005] As low molecular RNR inhibitors, there have so far been reportedpolyhydroxybenzoic acid derivatives (Published Japanese translation ofPCT international publication (Kohyo) No. 60-501409/1985), alkoxyphenolcompounds (Mol. Pharmacol., 45, pp.792-796), thiosemicarbazonederivatives (Biochem. Pharmacol., 48, pp.335-344), bipyridyl derivatives(Cancer Research, 53, pp.19-26) and the like. However, RNR inhibitoryactivity and anticancer activity of bisaryl derivatives have not beenreported. As for usefulness of bisaryl compounds composed of aryl groupslinked by means of plural sulfur atoms as anticancer agents, derivativescomprising aromatic benzenesulfonamide groups as the bisaryl moieties(Japanese Patent Publication (Kokoku) No. 42-10857/1967) have beenreported, and the synthesis of an anthramycin dimer has also beenreported (Tetrahedron Lett., 129, p.5105). It has also been known thatcertain bisaryl compounds have antiviral activity (Japanese PatentUnexamined Publication (Kokai) No. 5-501860/1993).

DISCLOSURE OF THE INVENTION

[0006] An object of the present invention is to provide a novelbisphenol compound useful as an active ingredient of a medicament.

[0007] Another object of the present invention is to provide anmedicament for treatment of cancer which comprises a bisphenol compoundhaving inhibitory activity against RNR as an active ingredient.

[0008] A still further object of the present invention is to provide anovel bisaryl compound useful as an active ingredient of a medicament.

[0009] The inventors of the present invention found that the compoundsof the present invention represented by the following formula haveinhibitory activity against RNR and anticancer activity, and thus theyare useful as an active ingredient of a medicament for treatment ofcancer. The present invention was achieved on the basis of thesefindings.

[0010] The present invention provides a medicament for treatment ofcancer which comprises a compound represented by the following generalformula (I):

Ar¹—S—R¹—S—Ar²

[0011] or a physiologically acceptable salt thereof,

[0012] wherein R¹ represents a nonmetal bridging group, Ar¹ and Ar²independently represent a group selected from the group consisting of anaryl group which has, on its ring, one or more hydroxyl groupsoptionally substituted with a monovalent group (the aryl group may haveone to three substituents other than a hydroxyl group on its ring), anda heteroaryl group which has, on its ring, one or more hydroxyl groupsoptionally substituted with a monovalent group (the heteroaryl group mayhave one to three substituents other than a hydroxyl group on its ring).

[0013] Preferred embodiments of the aforementioned invention providedare as follows:

[0014] the above medicament for treatment of cancer which comprises acompound represented by the aforementioned general formula (I) or aphysiologically acceptable salt thereof, wherein R¹ is represented bythe general formula (II):

—R²—N(R⁴)—R³—  (II)

[0015] wherein R² and R³ independently represent a divalent group, R⁴represents a monovalent group, and R⁴ may bind to R² or R³ to form acyclic structure; the above medicament for treatment of cancer whichcomprises the aforementioned compound or a physiologically acceptablesalt thereof, wherein R¹ is represented by the general formula (III):

—R⁵—X¹—R⁶—  (III)

[0016] wherein R⁵ and R⁶ independently represent a single bond or adivalent group not containing a nitrogen atom, X¹ represents an oxygenatom, S(O)_(k) wherein k represents an integer of from 0 to 2, or[(R⁹X²)_(m)(R¹⁰X³)_(n)(R¹¹X⁴)_(p)]_(q) wherein R⁹, R¹⁰, and R¹¹independently represent a single bond or a divalent group not containinga nitrogen atom, and wherein any groups selected from R⁵, R⁶, R⁹, R¹⁰and R¹¹ may bind together to form a cyclic structure, X², X³ and X⁴independently represent an oxygen atom, S(O)_(r) wherein r represents aninteger of from 0 to 2, or a single bond, and m, n, p and qindependently represent an integer of from 1 to 3;

[0017] the above medicament for treatment of cancer which comprises theaforementioned compound or a physiologically acceptable salt thereof,wherein R¹ is 2,6-pyridinediyldimethyl group (the pyridinediyldimethylgroup may have one to three substituents other than a hydrogen atom onits ring);

[0018] the above medicament for treatment of cancer which comprises theaforementioned compound or a physiologically acceptable salt thereof,wherein R² and R³ are the same divalent groups, and R⁴ is a C₁₋₄ alkylgroup which may have one to three substituents other than a hydrogenatom;

[0019] the above medicament for treatment of cancer which comprises theaforementioned compound or a physiologically acceptable salt thereof,wherein R² and R³ are the same divalent groups, R⁴ is represented asCOR²⁵ wherein R²⁵ represents a hydrogen atom, a C₁₋₄ alkyl group, anaryl group, a heteroaryl group, a heterocyclic group, an aralkyl group,or NR²⁶R²⁷ wherein R²⁶ and R²⁷ each represent a hydrogen atom, a C₁₋₄alkyl group, an aryl group, a heteroaryl group, a heterocyclic group, oran aralkyl group, and said alkyl group, aryl group, heteroaryl group,heterocyclic group, and aralkyl group including those for R²⁶ and R²⁷may have one to three substituents other than a hydrogen atom; and

[0020] the above medicament for treatment of cancer which comprises theaforementioned compound or a physiologically acceptable salt thereof,wherein R¹ is represented asR^(1A)-R^(1B)CO-R^(1C)-R^(1D)-R^(1C)-COR^(1B)-R^(1A) wherein R^(1A)represents a C₁₋₄ lower alkylene group, R^(1B) represents NH or amethylene group, R^(1C) represents a single bond or a methylene group,R^(1D) represent a divalent bridging cyclic hydrocarbon group, amonocyclic hydrocarbon group, or a heterocyclic group, and said bridgingcyclic hydrocarbon group, monocyclic hydrocarbon group, and heterocyclicgroup may have one to three substituents other than a hydrogen atom.

[0021] According to further preferred embodiments of the aforementionedeach invention provided are the above medicament for treatment of cancerwhich comprises the aforementioned compound or a physiologicallyacceptable salt thereof, wherein Ar¹ and Ar² independently represent theaforementioned aryl group; the above medicament for treatment of cancerwhich comprises the aforementioned compound or a physiologicallyacceptable salt thereof, wherein both of Ar¹ and Ar² are 4-hydroxyphenylgroups; the above medicament for treatment of cancer which comprises theaforementioned compound or a physiologically acceptable salt thereof,wherein R² and R³ are the same groups, and the minimum number ofbridge-forming atoms thereof is from 1 to 10, preferably 1 to 4; theabove medicament for treatment of cancer which comprises theaforementioned compound or a physiologically acceptable salt thereof,wherein R² and R³ are the same divalent groups optionally having abranched chain (said divalent groups may contain 1 to 3 oxygen atoms);the above medicament for treatment of cancer which comprises theaforementioned compound or a physiologically acceptable salt thereof,wherein the total number of carbon atoms is 35 or less; and the abovemedicament for treatment of cancer which comprises the aforementionedcompound or a physiologically acceptable salt thereof, which is used asa medicament for preventive and/or therapeutic treatment of a diseasecaused by over-expression of ribonucleotide reductase.

[0022] As another aspect of the present invention, provided is aribonucleotide reductase inhibitor or a selective cancer cellproliferation inhibitor which comprises a compound represented by theaforementioned general formula (I) or (II).

[0023] As further aspects of the present invention, provided are use ofthe aforementioned compound or a physiologically acceptable salt thereoffor the manufacture of the medicaments for treatment of cancer whichcomprise a compound represented by the aforementioned general formula(I) or (II), or a physiologically acceptable salt thereof as an activeingredient, preferably the medicaments for treatment of cancer in theform of a pharmaceutical composition comprising the aforementionedcompound or a physiologically acceptable salt thereof together with anadditive for pharmaceutical preparations; and a method for treatment ofcancer which comprises the step of administering a therapeuticallyeffective amount of a substance selected form the aforementionedcompound and a physiologically acceptable salt thereof to a patient.

[0024] The present invention further provides a compound represented bythe general formula (XII):

Ar²³—S—R²²—N(R²⁴)—R²³—S—Ar²⁴

[0025] or a salt thereof,

[0026] wherein, R²² and R²³ independently represent a divalent group,R²⁴ represents a monovalent group or a monovalent atom, and R²⁴ may bindto R²² and/or R²³ to form a cyclic structure, and may further bind toone or two C₁₋₄ alkylene groups to form a divalent group, and Ar²³ andAr²⁴ independently represent a group selected from the group consistingof an aryl group which has, on its ring, one to three hydroxyl groupsoptionally substituted with a monovalent group (the aryl group may haveone to three substituents other than a hydroxyl group on its ring), anda heteroaryl group which has, on its ring, one to three hydroxyl groupsoptionally substituted with a monovalent group (the heteroaryl group mayhave one to three substituents other than a hydroxyl group on its ring),provided that R²²-N(R²⁴)-R²³ except for the part of R²⁴ does not containan amide bond when R²² and R²³ do not form a ring, and provided thatwhen each of Ar²³ and Ar²⁴ is a phenyl group having one hydroxyl groupon the ring, not all of said phenyl groups have a tertiary alkyl groupat a position on the ring adjacent to the hydroxyl group.

[0027] As a preferred embodiment of the above invention, provided is theaforementioned compound or a salt thereof, wherein two or three groupsselected from the group consisting of R²², R²³ and R²⁴ form a ring orrings.

[0028] Further preferred embodiments provided are as follows:

[0029] the above compound or a salt thereof wherein R²² and R²³ are thesame divalent groups, and R²⁴ is a C₁-4 alkyl group which may have oneto three substituents other than a hydrogen atom;

[0030] the above compound or a salt thereof wherein R²² and R²³ are thesame divalent groups, R²⁴ is represented by COR¹²⁵ wherein R¹²⁵represents a hydrogen atom, a C₁₋₄ alkyl group, an aryl group, aheteroaryl group, a heterocyclic group, an aralkyl group, or NR¹²⁶R¹²⁷wherein R¹²⁶ and R¹²⁷ each represent a hydrogen atom, a C₁₋₄ alkylgroup, an aryl group, a heteroaryl group, a heterocyclic group, or anaralkyl group, and said alkyl group, aryl group, heteroaryl group,heterocyclic group, and aralkyl group including those for R¹²⁶ and R¹²⁷may have one to three substituents other than a hydrogen atom; and

[0031] the above compound or a salt thereof wherein R²²—N(R²⁴)—R²³ isrepresented byR^(101A)-R^(101B)CO-R^(101C)-R^(101D)-R^(101C)-COR^(101B)-R^(101A)wherein R^(101A) represents a C₁₋₄ lower alkylene group, R^(101B)represents NH or methylene group, R^(101C) represents a single bond or amethylene group, R^(101D) represent a divalent bridging cyclichydrocarbon group, a monocyclic hydrocarbon group, or a heterocyclicgroup, and said bridging cyclic hydrocarbon group, monocyclichydrocarbon group, and heterocyclic group may have one to threesubstituents other than a hydrogen atom.

[0032] Further preferred embodiments provided are as follows:

[0033] the above compound or a salt thereof wherein Ar²³ and Ar²⁴independently represents an aryl group which has, on its ring, one tothree hydroxyl groups optionally substituted with a monovalent group(the aryl group may have one to three substituents other than a hydroxylgroup on its ring);

[0034] the above compound or a salt thereof wherein both of Ar²³ andAr²⁴ independently represent a hydroxy-substituted phenyl group;

[0035] the above compound or a salt thereof wherein Ar²³ and Ar²⁴independently represent a monohydroxy-substituted phenyl group;

[0036] the above compound or a salt thereof wherein both of Ar²³ andAr²⁴ are 4-hydroxyphenyl groups;

[0037] the above compound or a salt thereof wherein the minimum numberof bridge-forming atoms of R²² and R² ³ are independently from 1 to 10[The term “minimum number of bridge-forming atoms” used herein means aminimum number of atoms that connect one atom and the other atom to bebridged. For example, the minimum number of bridge-forming atoms is 3for 1,3-propenylene group, 2 for 1,2-propenylene group, and 5 for1,5-(4-butoxy-3-pentenylene) group. Also for example, the number is 3for 1,3-phenylene group, 2 for 1,2-phenylene group, 3 for2,4-quinolinediyl group, and 4 for 1,5-naphthylene, as well as 4 forethylenedioxy group, 3 for malonyl group, and 4 for phthaloyl group.];

[0038] the above compound or a salt thereof wherein R²² and R²³ are thesame groups and each of the minimum numbers of bridge-forming atomsthereof is 1 to 10, preferably 1 to 4;

[0039] the above compound or a salt thereof wherein R²² and R²³independently represent methylene group, ethylene group, propylene groupor butylene group;

[0040] the above compound or a salt thereof wherein R²² and R²³ are thesame groups, and represent methylene group, ethylene group, propylenegroup or butylene group; and

[0041] the above compound or a salt thereof wherein the total number ofcarbon atoms is 35 or less.

BEST MODE FOR CARRYING OUT THE INVENTION

[0042] The groups that constitute the general formulas (I) and (II) willbe explained specifically.

[0043] The aryl group represented by Ar¹ and Ar² in the general formula(I) may be, for example, an aryl group having 6 to 12 carbon atoms,preferably phenyl group, naphthyl group or the like. The term “arylgroup” has the same meaning in the following description unlessotherwise indicated. The heteroaryl group may be, for example, aheteroaryl group having 5 to 12 ring-constituting atoms, such as pyridylgroup, pyrrolyl group, imidazolyl group, quinolinyl group, thienylgroup, and furyl group. As the heteroaryl group, for example, a groupcomprising a 5- or 6-membered nitrogen-containing or oxygen-containingheteroaryl ring having an enol type hydroxyl group and an active methineor active methylene group, such as pyrazolone ring and pyridone ring,may preferably used. The term “heteroaryl group” has the same meaning inthe following description unless otherwise indicated. It is preferredthat both of Ar¹ and Ar² are aryl groups, and it is more preferred thatboth of Ar¹ and Ar² are phenyl groups.

[0044] The number and the substituting position of the hydroxyl group orthe hydroxyl group substituted with a monovalent group on the ring ofthe aryl group or the heteroaryl group are not particularly limited, andthey preferably have one hydroxyl group. For example, when the arylgroup is phenyl group, phenyl group substituted with one hydroxyl groupat the p-position (4-position) may be exemplified. Examples of themonovalent group in the one to three hydroxyl groups substituted with amonovalent group present independently on the ring of the aryl group orthe heteroaryl group include, but not limited thereto, linear orbranched C₁₋₆ alkyl groups such as methyl group, ethyl group, n-propylgroup, isopropyl group, n-butyl group, sec-butyl group and tert-butylgroup; aryl groups such as phenyl group and naphthyl group; C₁₋₁₂alkanoyl groups which may be substituted; hydroxy(C₂₋₆)alkyl groups suchas hydroxyethyl group; C₇₋₁₅ aralkyl groups such as benzyl group andphenethyl group; C₆₋₁₂ aroyl groups; C₁₋₆ alkylsulfonyl groups; C₆₋₁₂arylsulfonyl groups; C₁₋₆ alkoxycarbonyl groups; aryloxycarbonyl groups;hydroxyphenylthio(C₁₋₆) alkyl groups; aminocarbonyl groups substitutedwith 0 to two C₁₋₆ alkyl groups or C₆₋₁₂ aryl groups; aminoalkylcarbonylgroups substituted with 0 to two C₁₋₆ alkyl groups or C₆₋₁₂ aryl groups;C₁₋₆ alkoxy-substituted C₁₋₆ alkanoyl groups, C₁₋₆alkylamino-substituted C₁₋₆ alkanoyl groups, piperidinocarbonyl group,4-pipe ridinopiperidinocarbonyl group, N-t-butoxycarbonyl-N-methylglycylgroup and the like.

[0045] On the ring of the aforementioned aryl group or the heteroarylgroup, one to three substituents other than a hydroxyl group or ahydroxyl group substituted with a monovalent group may be present. Assuch a substituent, examples which can be used are as follows: a halogenatom selected from fluorine atom, chlorine atom, bromine atom, andiodine atom; a C₁₋₆ alkyl group such as methyl group, ethyl group,n-propyl group, isopropyl group, n-butyl group, sec-butyl group andtert-butyl group; a halogenated C₁₋₆ alkyl group such as trifluoromethylgroup; a C₁₋₆ alkoxyl group such as methoxy group, ethoxy group,n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group andtert-butoxy group; a C₁₋₆ alkylenedioxy group such as methylenedioxygroup and ethylenedioxy group; carboxyl group; a C₁₋₆ alkoxycarbonylgroup; non-substituted amino group; a C₁₋₆ alkyl-substituted amino groupsuch as methylamino group, dimethylamino group and ethylamino group;cyano group or the like. Among them, halogen atoms, C₁₋₆ alkyl groups,C₁₋₆ alkoxyl groups and the like are preferred.

[0046] In the specification, the term “bridging group” means a group oran atom that can form two independent covalent bonds. In thespecification, the term “divalent group” means the bridging group whichcan form two independent covalent bonds, and contains at least onecarbon atom. The divalent group may have a chain-like or a cyclicstructure, or may have a combination of portions of a chain-likestructure and a cyclic structure.

[0047] R¹ in the general formula (I) represents a divalent groupconsisting of a nonmetal bridging group, which preferably comprisingatoms selected from the group consisting of carbon atom, hydrogen atom,oxygen atom, nitrogen atom, sulfur atom, and phosphorus atom, and hasatoms excluding hydrogen the number of which is 1 to 80. R¹ may furthercontain one to three halogen atoms.

[0048] These divalent groups may contain one to three unsaturated bonds,such as a double bond consisting of a carbon-carbon bond, carbon-oxygenbond, sulfur-oxygen bond, carbon-nitrogen bond, or nitrogen-nitrogenbond, or triple bond consisting of a carbon-carbon bond. Furthermore,they may contain one to three covalent bonds including any hetero atomssuch as carbamoyl bond, sulfamoyl bond, ether bond, and disulfide bondas a partial structure. For example, they may contain one to threecyclic structures selected from monocyclic structures such as thoseconsisting of benzene ring, cyclohexane ring, tetrahydrofuran ring, andpyranone ring, condensed rings such as naphthalene ring, indole ring,and quinoline ring, and bicyclo structures such as bicyclooctane ring.Furthermore, examples also include pyrrole ring, piperidine ring, indolering, pyridine ring, triazine ring, pyrimidine ring, quinoline ring,oxazine ring, indazole ring, thiazole ring and the like. When thedivalent group is a cyclic group or chain-like group, or when itcontains a partial chain-like structure, it may contain a branchedchain.

[0049] The aforementioned ring that constitutes the divalent group, andcarbon atoms and/or hetero atoms constituting the backbone of thedivalent group may have one or more substituents thereon, for example,those selected from the group consisting of a halogen atom such asfluorine atom, chlorine atom, and bromine atom; a linear or branchedC₁₋₆ alkyl group such as methyl group, ethyl group, n-propyl group,isopropyl group, n-butyl group, sec-butyl group, and tert-butyl group; alinear or branched C₁₋₆ alkoxyl group such as methoxy group, ethoxygroup, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxygroup and tert-butoxy group (those alkyl and alkoxyl groups may have asubstituent such as hydroxyl group, a C₁₋₆ alkoxyl group, a C₁₋₆alkyl-substituted or non-substituted carbamoyl group, non-substitutedamino group, a C₁₋₆ alkyl-substituted amino group such as methylaminogroup, dimethylamino group, and ethylamino group, a C₁₋₆ cyclic aminogroup such as morpholino group and piperidino group, and a C₁₋₆ cyclicaminocarbonyl group such as morpholino group and piperidino group); aC₁₋₆ alkylenedioxy group such as methylenedioxy group and ethylenedioxygroup; carboxyl group; a C₁₋₆ alkoxycarbonyl group; non-substitutedamino group or a C₁₋₆ alkyl-substituted amino group such as methylaminogroup, dimethylamino group and ethylamino group; hydroxyl group; an arylgroup such as phenyl group; a C₁₋₆ alkyl-substituted sulfonyl group; aC₁₋₆ alkanoyl group such as acetyl group and propionyl group; ahalogenated C₁₋₆ alkanoyl group such as trifluoroacetyl group andmonochloroacetyl group; an alkoxy-substituted C₁₋₆ alkanoyl group suchas methoxymethylcarbonyl group; cyano group; a C₁₋₆ alkyl-substituted ornon-substituted carbamoyl group; sulfamoyl group; carboxyl group; sulfogroup; a lactone ring or a lactam ring consisting of 4 to 8ring-constituting atoms; and a halogen atom.

[0050] Preferred examples of the divalent group represented by R¹include, for example, linear or branched C₁₋₆ alkylene groups such asmethylene group, ethylene group, propylene group, butylene group, andpentylene group; arylene groups such as p-phenylene group, m-phenylenegroup, 1,4-naphthylene group, and 1,5-naphthylene group; heteroarylenegroups such as 2,6-pyridinediyl group; vinylene group; ethynylene group;propenylene group; propynylene group; C₂₋₆ alkenylene groups such as1-butenylene group, and cis- and trans-2-butenylene group, C₂₋₆alkynylene groups and the like. These divalent groups may have one tothree substituents selected from the aforementioned substituents.Preferred examples of the alkylene group having one or more substituentsinclude, for example, oxo(C₁₋₆)alkylene groups such as 1-oxoethylenegroup, 1-oxo-2-methylethylene group, and 1-oxopropylene group; andoxy(C₁₋₆)alkylene groups such as 1-oxypropylene group, and2-oxypropylene group and the like. Divalent groups consisting of asuitable combination of groups selected from alkylene groups, arylenegroups and heteroarylene groups are also preferred.

[0051] Those wherein R¹ representsR^(1A)-R^(1B)CO-R^(1C)-R^(1D)-R^(1C)-COR^(1B)R^(1A), wherein R^(1A)represents a C₁₋₄ lower alkylene group, R^(1B) represents NH or amethylene group, R^(1C) represents a single bond or a methylene group,R^(1D) represents a divalent bridging cyclic hydrocarbon group, amonocyclic hydrocarbon group, or a heterocyclic group, and said bridgingcyclic hydrocarbon group, monocyclic hydrocarbon group, and heterocyclicgroup may have one to three substituents other than a hydrogen atom, arealso preferred examples of the divalent group. Examples of the divalentbridging cyclic hydrocarbon group and monocyclic hydrocarbon groupinclude, for example, 1,1-cyclopentylene, 5,6-norbornenylene,1,1-cyclopropylene, 1,1-cyclobutylene, 1,2-cyclobutylene,1,2-cyclopentylene, 2,2-dimethyl-1,3-cyclopentylene, 1,1-cyclohexylene,1,2-cyclohexylene, 1,3-cyclohexylene, 1,4-cyclohexylene,1,3-adamantylene, 1,1-phenylene, 1,2-phenylene, 1,3-phenylene,1,4-phenylene, 1,4-naphthylene, 2,3-naphthylene, 2,6-naphthylene,1,8-naphthylene and the like. Examples of the divalent heterocyclicgroup include, for example, 1,4-piperazinylene, 4-oxo-2,6-pyranylene,2,3-pyrrolylene, 3,5-pyrazolylene, 2,3-indolylene, 2,6-pyridylene,2,3-pyridylene, 2,4-pyridylene, 3,4-pyridylene, 2,5-pyridylene,3,5-pyridylene, 2, 3-pyrazinylene, 3, 4-furylene, 4, 5-imidazolylene,1,2, 3-triazol-4, 5-ylene, 7-oxabicyclo[2.2.1]heptynyl-2,3-ylene,tricyclo[4.2.1.0^(2.5)]nona-3,7-dien-3,4-ylene,2,2-dimethyldioxolan-4,5-ylene and the like. As preferred substituentson the divalent bridging cyclic hydrocarbon group, monocyclichydrocarbon group, and heterocyclic group, those exemplified for thesubstituents on the rings of the aforementioned aryl group andheteroaryl group may be used.

[0052] The minimum number of bridging group-forming atoms of R¹ ispreferably in the range of 1 to 20, more preferably 1 to 9, and mostpreferably 3 to 7. The total atom number of the whole compound of thegeneral formula (I) is preferably 50 or less.

[0053] The groups that constitute the compounds represented by thegeneral formula (II) will be specifically explained below.

[0054] The definition of the divalent group represented by R² and R³ isthe same as that of the divalent group represented by R¹ in the generalformula (I), provided that particularly preferred minimum number ofbridge-forming atoms of R² and R³ is in a range of from 1 to 3.

[0055] In the formula (II), R⁴ represents a monovalent group or amonovalent atom. R⁴ may be, for example, a hydrogen atom, hydroxylgroup, amidino group, amino group, an alkyl group which may besubstituted, an aryl group which may be substituted, a heteroaryl groupwhich may be substituted, an aralkyl group which may be substituted, analkyl group substituted with a heteroaryl group which may besubstituted, or a group represented by any one of the following formulas(XIII) to (XVI):

—CO—R²⁵  (XIII)

[0056] wherein R²⁵ represents a hydrogen atom, a C₁₋₄ alkyl group whichmay be substituted, an aryl group which may be substituted, a heteroarylgroup which may be substituted, a heterocyclic group which may besubstituted, or an aralkyl group which may be substituted;

—CO—NR²⁶R²⁷  (XIV)

[0057] wherein R²⁶ and R²⁷ independently represent a hydrogen atom, aC₁₋₄ alkyl group which may be substituted, an aryl group which may besubstituted, a heteroaryl group which may be substituted, a heterocyclicgroup which may be substituted, or an aralkyl group which may besubstituted;

—SO₂—R²⁵  (XV)

[0058] wherein R²⁵ has the same meaning as that defined above; and

—SO₂—NR²⁶R²⁷  (XVI)

[0059] wherein R²⁶ and R²⁷ have the same meanings as those definedabove.

[0060] Where R⁴ is an alkyl group which may be substituted, the alkylgroup may be linear or branched, and it may contain one or more cyclicstructures or one or more unsaturated bonds. The number of carbon atomsthereof may preferably be 20 or less including its substituent(s).Particularly preferred group may contain 1 to 4 carbon atoms. Preferredexamples of the substituent include, but not limited thereto, halogenatoms such as fluorine atom, chlorine atom, bromine atom, and iodineatom, hydroxyl group, carboxyl group, vinyl group, ethynyl group, C₃₋₈cycloalkyl groups, carbamoyl group which may have a substituent on thenitrogen atom (one or two substituents selected from a C₁₋₆ alkyl group,a halogenated C₁₋₆ alkyl group, a hydroxy-substituted C₁₋₆ alkyl group,an aryl group, a sulfonyl group, a C₁₋₆ alkyl-substituted sulfonylgroup, a C₁₋₆ alkanoyl group, a halogenated C₁₋₆ alkanoyl group, ahydroxy-substituted C₁₋₆ alkanoyl group, an alkoxy-substituted C₁₋₆alkanoyl group and the like), a sulfamoyl group which may have asubstituent on the nitrogen atom (one or two substituents selected fromthose exemplified for the aforementioned carbamoyl group), C₁₋₂₀alkanoyl groups, aroyl groups, heteroarylcarbonyl groups, C₁₋₂₀alkanoylamino groups, aroylamino groups, heteroarylcarbonylamino groups,C₁₋₂₀ alkylsulfonyl groups, arylsulfonyl groups, heteroarysulfonylgroups, C₁₋₂₀ alkylsulfonylamino groups, arylsulfonylamino groups,heteroarylsulfonylamino groups, an ureido group which may have asubstituent on the nitrogen atom (one or two substituents selected fromthose exemplified for the aforementioned carbamoyl group), a cyanogroup, an amino group which may have a substituent on the nitrogen atom(one or two substituents selected from those exemplified for theaforementioned carbamoyl group), C₁₋₂₀ alkylthio groups, C₁₋₂₀ alkoxylgroups, aryloxy groups, heteroaryloxy groups, arylthio groups, arylthiogroups substituted with one to three hydroxyl groups, C₁₋₂₀alkoxycarbonyl groups, aryloxycarbonyl groups, heteroaryloxycarbonylgroups, a 2-hydroxyethoxy group, polyether groups (2-methoxyethoxygroup, 2-(2-methoxyethoxy)ethoxy group etc.), a succinimido group, aguanidino group, aryl groups, aryl groups which are substituted with oneor two hydroxyl groups, aryl groups which are substituted with 1 to 5independently selected halogen atoms (a halogen atom has the samemeaning as that defined above), heteroaryl groups, heterocyclic groupsand the like.

[0061] The aryl group of the aforementioned aryl group, aroyl group,aroylamino group, arylsulfonyl group, arylsulfonylamino group, aryloxygroup, and aryloxycarbonyl group, and the heteroaryl group of theaforementioned heteroaryl group, heteroarylcarbonyl group,heteroarylsulfonyl group, heteroarylsulfonylamino group, heteroaryloxygroup, and heteroaryloxycarbonyl group have the same meanings as thosedefined above. Examples of the heterocyclic group include, for example,dioxolanyl group, morpholino group, morpholyl group, piperidyl group,dioxanyl group, imidazolyl group, thiazolyl group, pyrimidinyl group,2,2-dimethyl-1,3-dioxolanyl group and the like.

[0062] Preferred examples of R⁴ include, but not limited thereto, methylgroup, ethyl group, propyl group, sec-butyl group, cyclopropylmethylgroup, allyl group, propargyl group, 2-fluoroethyl group,2,2,2-trifluoroethyl group, 2-hydroxyethyl group, 3-hydroxypropyl group,carbamoylmethyl group, 2-carbamoylethyl group, 2-(N,N-dimethylcarbamoyl)ethyl group, 2-(N-morpholinocarbonyl)ethyl group,2-(N-piperidinocarbonyl)ethyl group, sulfamoylmethyl group, acetylmethylgroup, 2-(N-acetylamino)ethyl group, cyanomethyl group,2-(N,N-diethylamino)ethyl group, 2-(N-morpholino)ethyl group,2-(N-piperidino)ethyl group, 2-methylthioethyl group, 2-methoxyethylgroup, hydroxyethoxyethyl group, methoxycarbonylmethyl group and thelike.

[0063] When R⁴ is an aryl group which may be substituted, the number ofcarbon atom is preferably 20 or less including its substituent(s).Preferred examples include, for example, phenyl group which may besubstituted and naphthyl group which may be substituted. When thesegroups have a substituent, they may have one to three substituents.Preferred examples of the substituent are those exemplified as preferredsubstituents for R⁴ when it represents the alkyl group. Among them,halogen atoms, hydroxyl group, carbamoyl group and the like areparticularly preferred. When R⁴ is a heteroaryl group which may besubstituted, the number of carbon atoms is preferably 20 or lessincluding its substituent(s). Preferred examples include, for example,pyridyl group, thienyl group, furyl group, imidazolyl group, quinolylgroup and the like. These groups may have one to three substituentsselected from those exemplified as preferred substituents for R⁴ when itrepresents the alkyl group.

[0064] Where R⁴ is an aralkyl group which may be substituted or an alkylgroup substituted with a heteroaryl group which may be substituted, thenumber of carbon atoms thereof is preferably 20 or less including theirsubstituent(s). Preferred examples include, for example, benzyl group,2-phenylethyl group, naphthylmethyl group, 2-picolyl group, 3-picolylgroup, (2-furyl)methyl group, (2-thienyl)methyl group,(2-quinolyl)methyl group, 2-(2-pyridyl)ethyl group,2-(N-imidazolyl)ethyl group and the like. These groups may have one tothree substituents selected from those exemplified as preferredsubstituents for R⁴ when it represents the alkyl group. Among them,halogen atoms, hydroxyl group, carbamoyl group and the like areparticularly preferred substituents.

[0065] Where R⁴ is a group represented by the formula (XIII) or theformula (XV), the group represented by R²⁵ preferably has 15 or lesscarbon atoms, and it may have one to three substituents selected fromthose exemplified as preferred substituents for R⁴ when it representsthe alkyl group. The aryl group, heteroaryl group, heterocyclic groupand aralkyl group for R²⁵ have the same meanings as those defined above.Preferred examples of R⁴ include, for example, acetyl group, propionylgroup, benzoyl group, 2-pyridylcarbonyl group, 3-pyridylcarbonyl group,4-pyridylcarbonyl group, benzylcarbonyl group, methanesulfonyl group,benzenesulfonyl group and the like.

[0066] Where R⁴ is a group represented by the formula (XIV) or theformula (XVI), those groups represented by R²⁶ and R²⁷ preferably have15 or less carbon atoms, and they may have one to three substituentsselected from those exemplified as preferred substituents for R⁴ when itrepresents the alkyl group. In addition, R²⁶ and R²⁷ may bind to eachother to form a ring structure. Preferred examples of R⁴ include, forexample, aminocarbonyl group, N-methylaminocarbonyl group,N-phenylaminocarbonyl group, N-(2-pyridylamino)carbonyl group,N,N-dimethylaminocarbonyl group, N,N-diethylaminocarbonyl group,N-morpholinocarbonyl group, N-piperidinocarbonyl group, aminosulfonylgroup, N,N-dimethylaminosulfonyl group, N,N-diethylaminosulfonyl group,N-morpholinosulfonyl group, N-piperidinosulfonyl group and the like.

[0067] The ring structure which is formed by R⁴ together with R² or R³includes saturated and unsaturated ring structures. Examples of the ringinclude, for example, saturated or unsaturated 3- to 18-memberedmonocyclic rings or condensed rings, such as pyrrole ring, piperidinering, indole ring, pyridine ring, triazine ring, pyrimidine ring,quinoline ring, oxazine ring, indazole ring, and thiazole ring. Theserings may be partially or fully reduced or oxidized. Furthermore, theymay further bind to one or two C₁₋₄ alkylene groups to form a divalentgroup.

[0068] A compound in which one monovalent group such as an alkyl groupfurther bind to a nitrogen atom in the general formula (II) to form aquaternary salt of the nitrogen atom may also be used as an activeingredient of the medicament for treatment of cancer of the presentinvention. As a counter ion of the quaternary salt, for example, iodineion, bromine ion, chlorine ion, perchlorate ion, sulfate ion, phosphateion, sulfamate ion, acetate ion, lactate ion, citrate ion, tartrate ion,malonate ion, methanesulfonate ion, ethanesulfonate ion,hydroxyethanesulfonate ion, benzenesulfonate ion, p-toluenesulfonateion, and cyclohexylsulfamate ion may be used. Iodine ion, bromine ion,chlorine ion, and perchlorate ion can be preferably used. As themonovalent group, C₁₋₆ alkyl groups such as methyl group are preferred.

[0069] Divalent groups preferred as R¹, R², and R³ in the generalformula (I) and (II) will be exemplified blow. However, the divalentgroup which can be used for the compound as the active ingredient of themedicament for treatment of cancer of the present invention is notlimited to these examples (in the structures, Me represents methylgroup).

[0070] The bisaryl compounds represented by the aforementioned generalformula (I) have inhibitory activity against ribonucleotide reductase,and can selectively inhibit cancer cell proliferation. Therefore, theycan be used as an active ingredient of a medicament for treatment ofcancer, which can be administered to mammals including human. Types ofcancers to be treated by the medicament of the present invention are notparticularly limited, and the medicament can be applied to solid cancerssuch as stomach cancer, lung cancer, colon cancer, liver cancer, kidneycancer, breast cancer, uterus cancer, skin cancer and brain tumor, aswell as non-solid cancers such as leukemia and lymphoma.

[0071] In addition, they are also useful as an active ingredient ofmedicaments for preventive and/or therapeutic treatment of variousdiseases in mammals including human accompanied by unusual expression ofribonucleotide reductases deriving from host mammals themselves,viruses, bacteria and the like, for example, herpes syndrome caused byunusual proliferation of herpes simplex virus, acquired immunedeficiency syndrome caused by unusual proliferation of AIDS virus andthe like. Furthermore, the aforementioned compounds, per se, can also beused as ribonucleotide reductase inhibitors such as reagents in thefields of biochemistry, pharmacology, genetic engineering and the like.As the active ingredient of the medicament of the present invention, asubstance selected from the group consisting of the compounds of theaforementioned general formula (I) and salts thereof, and hydratesthereof and solvates thereof can be used, as well as any combinations oftwo or more of substances selected from said group.

[0072] Although the aforementioned substances, per se, may be used asthe medicament of the present invention, it is generally preferred thatthe medicament is provided for administration as a pharmaceuticalcomposition that can be prepared by using one or more pharmaceuticallyacceptable additives. Administration route of the medicament of thepresent invention is not particularly limited, and oral or parenteraladministration may be selected. Examples of the pharmaceuticalcompositions suitable for parenteral administration include, forexample, injections suitable for intravenous, intraarterial,intraperitoneal or intrapleural injection, drip infusions, preparationsfor intrarectal administration (suppositories) and the like. Examples ofthe pharmaceutical compositions suitable for oral administrationinclude, for example, tablets, capsules, granules, powders, syrups andthe like. However, applicable pharmaceutical compositions are notlimited to these examples, and those skilled in the art can select asuitable form of composition from available pharmaceutical compositions.

[0073] For example, for the manufacture of injections, theaforementioned substances as an active ingredient may be dissolved in adiluent available to those skilled in the art (for example,physiological saline, glucose solution for injection, lactose solutionfor injection, mannitol solution for injection and the like), and thenthe solution may be subjected to an appropriate sterilization treatmentsuch as filtration sterilization, and filled in hermetic containers suchas ampoules. Preparation for injection in a lyophilized form or powderfor injection mixed with sodium chloride may also be prepared accordingto the Japanese Pharmacopoeia. As the pharmaceutical additives, forexample, carriers such as auxiliaries such as polyethylene glycol andHCO-60 (surfactant; Nikko Chemical Co. Ltd.), ethanol and/or liposomeand cyclodextrin may be incorporated. Pharmaceutical compositionssuitable for oral administration or intrarectal administration can beprepared by mixing the aforementioned substances with appropriatepharmaceutical additives such as excipients, disintegrating agents,binders, lubricants, suspending agents, isotonic agents, and emulsifiersin a conventional manner, and formulating the mixture into anappropriate form.

[0074] Dosage and administration frequency of the medicament of thepresent invention are not particularly limited. When the medicament ofthe present invention is used for treatment of cancer, it can beadministered, for example, via intravenous route in an amount of 0.01 to100 mg/kg (based on the weight of the active ingredient) at intervals ofevery week to every 3 weeks. It is desirable to suitably adjust thedosage and administration frequency depending on various conditions, forexample, route of administration, a kind of an active ingredient, i.e.,the compound of the aforementioned formulas (I) to (III), the age andbody weight of patients, the condition, and frequency and severity ofside effects such as bone marrow suppression.

[0075] The bisaryl compounds represented by the aforementioned generalformula (I) may have one to three asymmetric carbons depending on thekind of the substituents. Furthermore, a sulfur atom may also serve asan asymmetric center. Any optical isomers in an optically pure formbased on one to three asymmetric carbons, any mixtures of theaforementioned optical isomers, and racemates, as well as diastereomersbased on two or more asymmetric carbons, any mixtures of suchdiastereomers and the like may be used as the active ingredient of themedicament of the present invention. As the active ingredient of themedicament of the present invention, those in free form encompassed bythe aforementioned formula as well as physiologically acceptable saltsthereof may be used.

[0076] Examples of such salts include, for example, hydrochlorides,sulfates, phosphates, sulfamates, acetates, lactates, citrates,tartrates, malonates, methanesulfonates, ethanesulfonates,hydroxyethanesulfonates, benzenesulfonates, p-toluenesulfonates,cyclohexylsulfamates and the like. These salts can be prepared bydissolving the aforementioned compound as free base in water, an aqueousorganic solvent such as alcoholic solvent or a suitable organic solventcontaining a corresponding acid to form a uniform solution, andisolating a salt after evaporation of water or the organic solvent, orallowing the compound in free form to react with an acid in an organicsolvent. In the latter case, for example, the resulting salt can bedirectly isolated, or recovered by evaporation of the solvent. As theactive ingredient of the medicament of the present invention, theaforementioned compounds in free form and salts thereof, and inaddition, hydrates thereof and solvates thereof can be used. Examples ofthe organic solvent for forming the solvates include, for example,physiologically acceptable solvents such as ethanol and ethylene glycol.

[0077] Specific examples of the compounds most suitably used for themedicament of the present invention will be listed below. However, theactive ingredient of the medicament of the present invention is notlimited to the following compounds (in the tables, the serial numbers inthe first left column indicate the compound numbers, Ph representsphenyl group, and p-HO-Ph represents p-hydroxyphenyl group. In Table 3,“B” represents p-hydroxyphenylthio group, Me represents methyl group, Etrepresents ethyl group, and Ac represents acetyl group). TABLE 1Compound No. 1

Compound No. 2

Compound No. 3

Compound No. 4

Compound No. 5

Compound No. 6

Compound No. 7

Compound No. 8

Compound No. Ar¹ R¹ Ar¹  9 p-HO—Ph— —C₂H₄—S—C₂H₄— p-HO—Ph— 10 p-HO—Ph——C₂H₄—S—C₃H₆— p-HO—Ph— 11 p-HO—Ph— —C₂H₄—S—C₄H₄— p-HO—Ph— 12 p-HO—Ph——C₂H₄—S—C₄H₆— p-HO—Ph— 13 p-HO—Ph— —C₂H₄—S—C₄H₈— p-HO—Ph— 14 p-HO—Ph——C₃H₆—S—C₃H₆— p-HO—Ph— 15 p-HO—Ph— —C₃H₆—S—C₄H₆— p-HO—Ph— 16 p-HO—Ph——C₃H₆—S—C₄H₈— p-HO—Ph— 17 p-HO—Ph— —C₄H₈—S—C₄H₈— p-HO—Ph— 18 p-HO—Ph——CH₂CO—S—C₂H₄— p-HO—Ph— 19 p-HO—Ph— —CH₂CO—S—C₃H₆— p-HO—Ph— 20 p-HO—Ph——CH₂CO—S—C₄H₈— p-HO—Ph— 21 p-HO—Ph— —CH₂CO—S—C₄H₆— p-HO—Ph— 22 p-HO—Ph——CH₂CO—S—C₄H₄— p-HO—Ph— 23 p-HO—Ph— —CH(CH₃)CO—S—C₂H₄— p-HO—Ph— 24p-HO—Ph— —C₂H₄CO—S—CH₂CH(OH)CH₂— p-HO—Ph— 25 p-HO—Ph——CH₂CO—S—C₂H₄NHCOCH₂— p-HO—Ph— 26 p-HO—Ph— —C₂H₄CO—S—C₂H₄NHCOC₂H₄—p-HO—Ph— 27 p-HO—Ph— —C₂H₄—O—C₂H₄— p-HO—Ph— 28 p-HO—Ph— —C₂H₄—O—C₃H₆—p-HO—Ph— 29 p-HO—Ph— —C₂H₄—O—C₄H₄— p-HO—Ph— 30 p-HO—Ph— —C₂H₄—O—C₄H₆—p-HO—Ph— 31 p-HO—Ph— —C₂H₄—O—C₄H₈— p-HO—Ph— 32 p-HO—Ph— —C₃H₆—O—C₃H₆—p-HO—Ph— 33 p-HO—Ph— —C₃H₆—O—C₄H₆— p-HO—Ph— 34 p-HO—Ph— —C₃H₆—O—C₄H₈—p-HO—Ph— 35 p-HO—Ph— —C₄H₈—O—C₄H₈— p-HO—Ph— 36 p-HO—Ph— —CH₂CO—O—C₂H₄—p-HO—Ph— 37 p-HO—Ph— —CH₂CO—O—C₃H₆— p-HO—Ph— 38 p-HO—Ph— —CH₂CO—O—C₄H₈—p-HO—Ph— 39 p-HO—Ph— —CH₂CO—O—C₄H₆— p-HO—Ph— 40 p-HO—Ph— —CH₂CO—O—C₄H₄—p-HO—Ph— 41 p-HO—Ph— —CH(CH₃)CO—O—C₂H₄— p-HO—Ph— 42 p-HO—Ph——C₂H₄CO—O—CH₂CH(OH)CH₂— p-HO—Ph— 43 p-HO—Ph— —CH₂CO—O—C₂H₄NHCOCH₂—p-HO—Ph— 44 p-HO—Ph— —C₂H₄CO—O—C₂H₄NHCOC₂H₄— p-HO—Ph—

[0078] TABLE 2 Compound No. Ar¹ R² R³ R⁴ Ar² 45 p-HO—Ph— —C₂H₄— —C₂H₄——H p-HO—Ph— 46 p-HO—Ph— —C₃H₆— —C₃H₆— —H p-HO—Ph— 47 p-HO—Ph— —C₄H₈——C₄H₈— —H p-HO—Ph— 48 p-HO—Ph— —C₂H₄— —C₂H₄— —OH p-HO—Ph— 49 p-HO—Ph——C₂H₄— —C₂H₄— —C(═NH)NH₂ p-HO—Ph— 50 p-HO—Ph— —C₂H₄— —C₂H₄— —COC₃H₇p-HO—Ph— 51 p-HO—Ph— —C₂H₄— —C₂H₄— —COCH₂CH₂CO₂H p-HO—Ph— 52 p-HO—Ph——C₂H₄— —C₂H₄— —COCH₂CH₂S—Ph—OH-p p-HO—Ph— 53 p-HO—Ph— —C₂H₄— —C₂H₄— —CHOp-HO—Ph— 54 p-HO—Ph— —C₂H₄— —C₂H₄— —COCH₃ p-HO—Ph— 55 p-HO—Ph— —C₂H₄——C₂H₄— —SO₂CH₃ p-HO—Ph— 56 p-HO—Ph— —C₃H₆— —C₃H₆— —CHO p-HO—Ph— 59p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂CH₂NH₂ p-HO—Ph— 60 p-HO—Ph— —CH₂CO— —C₂H₄— —Hp-HO—Ph— 61 p-HO—Ph— —CH₂CO— —C₃H₆— —H p-HO—Ph— 62 p-HO—Ph— —CH₂CO——C₄H₈— —H p-HO—Ph— 63 p-HO—Ph— —CH₂CO— —C₄H₆— —H p-HO—Ph— 64 p-HO—Ph——CH₂CO— —C₄H₄— —H p-HO—Ph— 65 p-HO—Ph— —CH₂CO— —C₄H₄— —CHO p-HO—Ph— 66p-HO—Ph— —CH(CH₃)CO— —C₂H₄— —H p-HO—Ph— 67 p-HO—Ph— —CH(CH₃)CO— —C₂H₄——C₂H₄OH p-HO—Ph— 68 p-HO—Ph— —C₂H₄CO— —CH₂CH(OH)CH₂— —C₂H₄OH p-HO—Ph— 69p-HO—Ph— —CH₂CO— —C₂H₄NHCOCH₂— —H p-HO—Ph— 70 p-HO—Ph— —C₂H₄CO——C₂H₄NHCOC₂H₄— —H p-HO—Ph— 71 p-HO—Ph— —C₂H₄— —C₂H₄— —C₂H₅ p-HO—Ph— 72p-HO—Ph— —C₂H₄— —C₂H₄— —C₃H₇ p-HO—Ph— 73 p-HO—Ph— —C₂H₄— —C₂H₄——CH₂—C≡CH p-HO—Ph— 74 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂—CH═CH₂ p-HO—Ph— 75p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂-cyclopropyl p-HO—Ph— 76 p-HO—Ph— —C₂H₄——C₂H₄— —CH₂—SO₂NH₂ p-HO—Ph— 77 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂—CN p-HO—Ph—78 p-HO—Ph— —C₂H₄— —C₂H₄— —C₂H₄—CO—NH₂ p-HO—Ph— 79 p-HO—Ph— —C₂H₄——C₂H₄— —C₂H₄—CO—N(CH₃)₂ p-HO—Ph— 80 p-HO—Ph— —C₂H₄— —C₂H₄——C₂H₄—CO—N(C₂H₅)₂ p-HO—Ph— 81 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂—CO—CH₃p-HO—Ph— 82 p-HO—Ph— —C₂H₄— —C₂H₄— —C₂H₄—NH—CO—NH₂ p-HO—Ph— 83 p-HO—Ph——C₂H₄— —C₂H₄— —C₂H₄—NH—CO—CH₃ p-HO—Ph— 84 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂Fp-HO—Ph— 85 p-HO—Ph— —C₂H₄— —C₂H₄— —CF₃ p-HO—Ph— 86 p-HO—Ph— —C₂H₄——C₂H₄— —C₂H₄—(N-succinimido) p-HO—Ph— 87 p-HO—Ph— —C₂H₄— —C₂H₄——C₂H₄—S—CH₃ p-HO—Ph— 88 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂-ethyleneacetalp-HO—Ph— 89 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂-(2-thienyl) p-HO—Ph— 90 p-HO—Ph——C₂H₄— —C₂H₄— -furfuryl p-HO—Ph— 91 p-HO—Ph— —C₂H₄— —C₂H₄——CH₂-(4-pyridyl) p-HO—Ph— 92 p-HO—Ph— —C₂H₄— —C₂H₄— -o-hydroxybenzylp-HO—Ph— 93 p-HO—Ph— —C₂H₄— —C₂H₄— -m-hydroxybenzyl p-HO—Ph— 94 p-HO—Ph——C₂H₄— —C₂H₄— -p-hydroxybenzyl p-HO—Ph— 95 p-HO—Ph— —C₂H₄— —C₂H₄——(CH₂)₃—OH p-HO—Ph— 96 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂—NH—CO—CH₃ p-HO—Ph— 97p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂—CO—NH₂ p-HO—Ph— 98 p-HO—Ph— —C₂H₄— —C₂H₄—-benzyl p-HO—Ph— 99 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂-(3-pyridyl) p-HO—Ph— 100p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂-(2-pyridyl) p-HO—Ph— 101 p-HO—Ph— —C₂H₄——C₂H₄— —CH₂-(2-quinolinyl) p-HO—Ph— 102 p-HO—Ph— —C₂H₄— —C₂H₄— —C₂H₄—OHp-HO—Ph— 103 p-HO—Ph— —C₂H₄— —C₂H₄— —(CH₂)₃—OCH₃ p-HO—Ph— 104 p-HO—Ph——C₂H₄— —C₂H₄— —C₂H₄—OCH₃ p-HO—Ph— 105 p-HO—Ph— —C₂H₄— —C₂H₄—-o-fluorobenzyl p-HO—Ph— 106 p-HO—Ph— —C₂H₄— —C₂H₄— -p-fluorobenzylp-HO—Ph— 107 p-HO—Ph— —C₂H₄— —C₂H₄— —C₂H₄—CO—(N-morpholino) p-HO—Ph— 108p-HO—Ph— —C₂H₄— —C₂H₄— —C₂H₄—CO-(1-piperidyl) p-HO—Ph— 109 p-HO—Ph——C₂H₄— —C₂H₄— —C₂H₄—N(C₂H₅)₂ p-HO—Ph— 110 p-HO—Ph— —C₂H₄— —C₂H₄——C₂H₄—(N-morpholino) p-HO—Ph— 111 p-HO—Ph— —C₂H₄— —C₂H₄——C₂H₄-(1-piperidyl) p-HO—Ph— 112 p-HO—Ph— —C₂H₄— —C₂H₄— —CO—CH₃ p-HO—Ph—113 p-HO—Ph— —C₂H₄— —C₂H₄— —CO—C₂H₅ p-HO—Ph— 114 p-HO—Ph— —C₂H₄— —C₂H₄——CO—C₆H₅ p-HO—Ph— 115 p-HO—Ph— —C₂H₄— —C₂H₄— —CO-(2-pyridyl) p-HO—Ph—116 p-HO—Ph— —C₂H₄— —C₂H₄— —CO-(3-pyridyl) p-HO—Ph— 117 p-HO—Ph— —C₂H₄——C₂H₄— —CO-(4-pyridyl) p-HO—Ph— 118 p-HO—Ph— —C₂H₄— —C₂H₄— —SO₂—CH₃p-HO—Ph— 119 p-HO—Ph— —C₂H₄— —C₂H₄— —SO₂—C₆H₅ p-HO—Ph— 120 p-HO—Ph——C₂H₄— —C₂H₄— —CO—NH₂ p-HO—Ph— 121 p-HO—Ph— —C₂H₄— —C₂H₄— —CO—NH(CH₃)p-HO—Ph— 122 p-HO—Ph— —C₂H₄— —C₂H₄— —CO—N(CH₃)₂ p-HO—Ph— 123 p-HO—Ph——C₂H₄— —C₂H₄— —CO—N(C₂H₅)₂ p-HO—Ph— 124 p-HO—Ph— —C₂H₄— —C₂H₄——CO-(N-morpholino) p-HO—Ph— 125 p-HO—Ph— —C₂H₄— —C₂H₄— —CO-(1-piperidyl)p-HO—Ph— 126 p-HO—Ph— —C₂H₄— —C₂H₄— —CO—NH—C₆H₅ p-HO—Ph— 127 p-HO—Ph——C₂H₄— —C₂H₄— —CO—NH-(2-pyridyl) p-HO—Ph— 128 p-HO—Ph— —C₂H₄— —C₂H₄——SO₂—NH₂ p-HO—Ph— 129 p-HO—Ph— —C₂H₄— —C₂H₄— —SO₂—N(C₂H₅)₂ p-HO—Ph— 130p-HO—Ph— —C₂H₄— —C₂H₄— —SO₂-(N-morpholino) p-HO—Ph— Compound No. 57

Compound No. 58

[0079] TABLE 3 131 B—B 132 B—CH₂—B 133 B—C₂H₄—B 134 B—C₃H₆—B 135B—C₄H₈—B 136 B—C₅H₁₀—B 137 B—C₆H₁₂—B 138 B—C₇H₁₄—B 139 B—C₈H₁₆—B 140B—C₉H₁₈—B 141 B—C₁₀H₂₀—B 142 B—C₁₁H₂₂—B 143 B-C₂H₄—SO₂—C₂H₄—SO₂—C₂H₄—B144 B—CH(CH₃)—B 145 B—CH(C₂H₅)—B 146 B—CH(n-C₃H₇)—B 147 B—CH(C₆H₅)—B 148B—CH(B)(p-HOC₂H₄O—C₆H₄—) 149 B—C(CH₃)₂—B 150 B—CH(COOH)—B 151B—CH(C₂H₄OH)—B 152 B—CH(CH₃)—CH₂—B 153 B—CH(C₂H₄OH)—CH₂—B 154B—CH(COOH)—CH₂—B 155 B—CH(C₂H₅)—CH₂—B 156 B—CH₂—CH(OH)—CH₂—B 157B—CH₂—C(CH₂B)₂—CH₂—B 158 B—CH₂—S—CH₂—B 159 B—CH₂—CH═CH—CH₂—B 160B—CH₂—C≡C—CH₂—B 161 B—CH₂—C₆H₄—CH₂—B(—C₆H₄— is a o-phenylene group) 162B—C₂H₄—O—CH₂—O—C₂H₄—B 163 B—C₂H₄—O—C₂H₄—O—C₂H₄—B 164B—CH₂—COO—C₂H₄—OCOCH₂—B 165 B—CH₂—COO—C₃H₆—OCOCH₂—B 166B—CH₂CH(OH)CH₂—O—C₂H₄—O—CH₂CH(OH)CH₂—B 167B—(C₂H₄O)₂—CO—CH₂—CO—(C₂H₄O)₂—B 168B—(C₂H₄O)₂—CO-(trans)CH═CH—CO—(C₂H₄O)₂—B 169 B—CH₂—COO—(C₂H₄O)₃—CO—CH₂—B170 B—CH₂—COO—(C₂H₄O)4-CO—CH₂—B 171 B—(C₂H₄O)₃—C₂H₄—B 172B—(C₂H₄O)₄—C₂H₄—B 173 B—(C₂H₄O)₅—C₂H₄—B 174 B—(C₂H₄O)₃—CO—(C₂H₄O)₃—B 175B—(C₂H₄O)₂—CO—C₂H₄—CO—(C₂H₄O)₂—B Compound No. 176

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Compound No. 185

[B—CH₂—CO—]₂ Compound No. 186 B—CO—CH₂—CO—B Compound No. 187

X = CH₂ =O Compound No. 188 Compound No. 189 Compound No. 190

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[0080] According to the present invention, there are provided novelcompounds represented by the general formula (XII):

Ar²³—S—R²²—N(R²⁴)—R²³—S—Ar²⁴.

[0081] Ar²³ and Ar²⁴ in the general formula (XII) have the same meaningsas the aforementioned Ar¹ and Ar². However, those wherein each of Ar²³and Ar²⁴ is a phenyl group having one hydroxyl group on the ring, andboth of these phenyl groups have a tertiary alkyl group at a position onthe ring adjacent to the hydroxyl group are excluded from the scope ofthe invention concerning the novel compounds of the present invention.R²², R²³ and R²⁴ in the general formula (XII) have the same meanings asthe aforementioned R², R³, and R⁴, provided that, when R²² and R²³ donot form a ring. R²²—N(R²⁴)—R²³ except for the part of R²⁴ does notcontain an amide bond. Furthermore, in the above definitions, R¹²⁵,R¹²⁶, R¹²⁷, R^(101A), R^(101B), R^(101C), and R^(101D) have the samemeanings as R²⁵, R²⁶, R²⁷, R^(1A), R^(1B), R^(1C) and R^(1D),respectively.

[0082] Examples of the divalent group suitable as R²², R²³, orR²²—N(R²⁴)—R²³ will be exemplified below. However, the divalent groupwhich can be used for the compound of the present invention is notlimited to these examples.

[0083] Particularly preferred compounds of the present inventionrepresented by the formula (XII) will be specifically exemplified below.However, the compounds of the present invention are not limited to thefollowing exemplary compounds. TABLE 4 Compound No. Ar²³ R²² R²³ R²⁴Ar²⁴ 45 p-HO—Ph— —C₂H₄— —C₂H₄— —H p-HO—Ph— 46 p-HO—Ph— —C₃H₆— —C₃H₆— —Hp-HO—Ph— 47 p-HO—Ph— —C₄H₈— —C₄H₈— —H p-HO—Ph— 48 p-HO—Ph— —C₂H₄— —C₂H₄——OH p-HO—Ph— 49 p-HO—Ph— —C₂H₄— —C₂H₄— —C(═NH)NH₂ p-HO—Ph— 50 p-HO—Ph——C₂H₄— —C₂H₄— —COC₃H₇ p-HO—Ph— 51 p-HO—Ph— —C₂H₄— —C₂H₄— —COCH₂CH₂CO₂Hp-HO—Ph— 52 p-HO—Ph— —C₂H₄— —C₂H₄— —COCH₂CH₂S—Ph—OH-p p-HO—Ph— 53p-HO—Ph— —C₂H₄— —C₂H₄— —CHO p-HO—Ph— 54 p-HO—Ph— —C₂H₄— —C₂H₄— —COCH₃p-HO—Ph— 55 p-HO—Ph— —C₃H₆— —C₃H₆— —CHO p-HO—Ph— 56 p-HO—Ph— —C₃H₆——C₃H₆— —COCH₂Cl p-HO—Ph— 59 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂CH₂NH₂ p-HO—Ph—71 p-HO—Ph— —C₂H₄— —C₂H₄— —C₂H₅ p-HO—Ph— 72 p-HO—Ph— —C₂H₄— —C₂H₄— —C₃H₇p-HO—Ph— 73 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂—C≡CH p-HO—Ph— 74 p-HO—Ph— —C₂H₄——C₂H₄— —CH₂—CH═CH₂ p-HO—Ph— 75 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂-cyclopropylp-HO—Ph— 76 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂—SO₂NH₂ p-HO—Ph— 77 p-HO—Ph——C₂H₄— —C₂H₄— —CH₂—CN p-HO—Ph— 78 p-HO—Ph— —C₂H₄— —C₂H₄— —C₂H₄—CO—NH₂p-HO—Ph— 79 p-HO—Ph— —C₂H₄— —C₂H₄— —C₂H₄—CO—N(CH₃)₂ p-HO—Ph— 80 p-HO—Ph——C₂H₄— —C₂H₄— —C₂H₄—CO—N(C₂H₅)₂ p-HO—Ph— 81 p-HO—Ph— —C₂H₄— —C₂H₄——CH₂—CO—CH₃ p-HO—Ph— 82 p-HO—Ph— —C₂H₄— —C₂H₄— —C₂H₄—NH—CO—NH₂ p-HO—Ph—83 p-HO—Ph— —C₂H₄— —C₂H₄— —C₂H₄—NH—CO—CH₃ p-HO—Ph— 84 p-HO—Ph— —C₂H₄——C₂H₄— —CH₂F p-HO—Ph— 85 p-HO—Ph— —C₂H₄— —C₂H₄— —CF₃ p-HO—Ph— 86p-HO—Ph— —C₂H₄— —C₂H₄— —C₂H₄-(N-succinimido) p-HO—Ph— 87 p-HO—Ph— —C₂H₄——C₂H₄— —C₂H₄—S—CH₃ p-HO—Ph— 88 p-HO—Ph— —C₂H₄— —C₂H₄——CH₂-ethyleneacetal p-HO—Ph— 89 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂-(2-thienyl)p-HO—Ph— 90 p-HO—Ph— —C₂H₄— —C₂H₄— -furfuryl p-HO—Ph— 91 p-HO—Ph— —C₂H₄——C₂H₄— —CH₂-(4-pyridyl) p-HO—Ph— 92 p-HO—Ph— —C₂H₄— —C₂H₄—-o-hydroxybenzyl p-HO—Ph— 93 p-HO—Ph— —C₂H₄— —C₂H₄— -m-hydroxybenzylp-HO—Ph— 94 p-HO—Ph— —C₂H₄— —C₂H₄— -p-hydroxybenzyl p-HO—Ph— 95 p-HO—Ph——C₂H₄— —C₂H₄— —(CH₂)₃—OH p-HO—Ph— 96 p-HO—Ph— —C₂H₄— —C₂H₄——CH₂—NH—CO—CH₃ p-HO—Ph— 97 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂—CO—NH₂ p-HO—Ph—98 p-HO—Ph— —C₂H₄— —C₂H₄— -benzyl p-HO—Ph— 99 p-HO—Ph— —C₂H₄— —C₂H₄——CH₂-(3-pyridyl) p-HO—Ph— 100 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂-(2-pyridyl)p-HO—Ph— 101 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂-(2-quinolinyl) p-HO—Ph— 102p-HO—Ph— —C₂H₄— —C₂H₄— —C₂H₄—OH p-HO—Ph— 103 p-HO—Ph— —C₂H₄— —C₂H₄——(CH₂)₃—OCH₃ p-HO—Ph— 104 p-HO—Ph— —C₂H₄— —C₂H₄— —C₂H₄—OCH₃ p-HO—Ph— 105p-HO—Ph— —C₂H₄— —C₂H₄— -o-fluorobenzyl p-HO—Ph— 106 p-HO—Ph— —C₂H₄——C₂H₄— -p-fluorobenzyl p-HO—Ph— 107 p-HO—Ph— —C₂H₄— —C₂H₄——C₂H₄—CO—(N-morpholino) p-HO—Ph— 108 p-HO—Ph— —C₂H₄— —C₂H₄——C₂H₄—CO-(1-piperidyl) p-HO—Ph— 109 p-HO—Ph— —C₂H₄— —C₂H₄——C₂H₄—N(C₂H₅)₂ p-HO—Ph— 110 p-HO—Ph— —C₂H₄— —C₂H₄— —C₂H₄—(N-morpholino)p-HO—Ph— 111 p-HO—Ph— —C₂H₄— —C₂H₄— —C₂H₄-(1-piperidyl) p-HO—Ph— 112p-HO—Ph— —C₂H₄— —C₂H₄— —CO—CH₃ p-HO—Ph— 113 p-HO—Ph— —C₂H₄— —C₂H₄——CO—C₂H₅ p-HO—Ph— 114 p-HO—Ph— —C₂H₄— —C₂H₄— —-CO—C₆H₅ p-HO—Ph— 115p-HO—Ph— —C₂H₄— —C₂H₄— —CO-(2-pyridyl) p-HO—Ph— 116 p-HO—Ph— —C₂H₄——C₂H₄— —CO-(3-pyridyl) p-HO—Ph— 117 p-HO—Ph— —C₂H₄— —C₂H₄——CO-(4-pyridyl) p-HO—Ph— 118 p-HO—Ph— —C₂H₄— —C₂H₄— —SO₂—CH₃ p-HO—Ph—119 p-HO—Ph— —C₂H₄— —C₂H₄— —SO₂—C₆H₅ p-HO—Ph— 120 p-HO—Ph— —C₂H₄— —C₂H₄——CO—NH₂ p-HO—Ph— 121 p-HO—Ph— —C₂H₄— —C₂H₄— —CO—NH(CH₃) p-HO—Ph— 122p-HO—Ph— —C₂H₄— —C₂H₄— —CO—N(CH₃)₂ p-HO—Ph— 123 p-HO—Ph— —C₂H₄— —C₂H₄——CO—N(C₂H₅)₂ p-HO—Ph— 124 p-HO—Ph— —C₂H₄— —C₂H₄— —CO-(N-morpholino)p-HO—Ph— 125 p-HO—Ph— —C₂H₄— —C₂H₄— —CO-(1-piperidyl) p-HO—Ph— 126p-HO—Ph— —C₂H₄— —C₂H₄— —CO—NH—C₆H₅ p-HO—Ph— 127 p-HO—Ph— —C₂H₄— —C₂H₄——CO—NH-(2-pyridyl) p-HO—Ph— 128 p-HO—Ph— —C₂H₄— —C₂H₄— —SO₂—NH₂ p-HO—Ph—129 p-HO—Ph— —C₂H₄— —C₂H₄— —SO₂—N(C₂H₅)₂ p-HO—Ph— 130 p-HO—Ph— —C₂H₄——C₂H₄— —SO₂-(N-morpholino) p-HO—Ph— Compound No. 57

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Compound No. 227

Compound No. 228

[0084] The compounds of the present invention may form an acid additionsalt, and may also form a base addition salt depending on the types ofsubstituents. Examples of the acid addition salt include, but notlimited thereto, mineral acid salts such as hydrochlorides, sulfates andnitrates, and organic acid salts such as p-toluenesulfonates,methanesulfonates, acetates, chloroacetates, oxalates,trifluoromethanesulfonates, and quinolinesulfonates. When they form abase addition salt, metal salts such as sodium salts and potassiumsalts, ammonium salts such as ammonium salts and triethylammonium saltsand the like may be used. The compounds of the present invention mayalso form intramolecular zwitter ions based on a phenolic hydroxyl groupand a basic group, which also fall within the scope of the presentinvention. Furthermore, the compounds of the aforementioned formula (XI)and formula (XII) in free form or any salts thereof, and any hydrates orany solvates of the compounds in free form or salts thereof fall withinthe scope of the present invention. Solvents that can form solvates arenot particularly limited. For example, the solvate may be formed withmethanol, ethanol, acetone, tetrahydrofuran, dichloromethane,chloroform, dimethylformamide or the like.

[0085] The compounds of the present invention may have one or moreasymmetric carbons depending on the types of the substituents.Furthermore, a sulfur atom may also serve as an asymmetric center. Anyoptical isomers in optically pure form based on one or more asymmetriccarbons, mixtures of the optical isomers, racemates, diastereomers basedon two or more asymmetric carbons, mixtures of the diastereomers and thelike all fall within the scope of the present invention.

[0086] Two or three groups selected from R²², R²³, and R²⁴ may bind toeach other, via a divalent group if required, to form a saturated orunsaturated cyclic structure. In that case, the nitrogen atom to whichR²⁴ binds may be an atom that constitutes the ring. Examples of the ringinclude, for example, pyrrole ring, piperidine ring, indole ring,pyridine ring, triazine ring, pyrimidine ring, quinoline ring, oxazinering, indazole ring, thiazole ring and the like. These rings may have apartially or completely reduced ring structure. Furthermore, thosewherein one more monovalent group such as an alkyl group further bindsto the nitrogen atom to which R²⁴ binds to form a quaternary salt alsofall within the scope of the present invention. The counter ion of thequaternary salt may be, for example, iodide ion, bromide ion, chlorideion, perchlorate ion and the like. As the monovalent group, C₁₋₆ alkylgroups such as methyl group and the like are preferred.

[0087] The methods for preparing the bisaryl compounds represented bythe aforementioned general formulas (I), (II) and (XII) are notparticularly limited, and they can be synthesized via various syntheticroutes. Methods for preparing typical compounds of the present inventionare specifically disclosed in Examples set out below, and accordingly,those skilled in the art will readily prepare bisaryl compounds fallingwithin the scopes of the aforementioned general formulas by referring tothe method described in Examples, adding suitable alterations andmodifications to the methods, if required, and suitably choosingstarting materials and reagents. For the preparation, one step, orseveral combined steps selected from various condensation, addition,oxidation, and reduction reactions and the like can be used. Thesereactions are detailed in literature. For example, various methodsmentioned as unit operations and starting materials disclosed in “JikkenKagaku Koza” (Maruzen Co., Ltd., each separate volume of the first tothe 4th edition are available) can be preferably used.

[0088] For example, it may be preferable to use a mercapto compound, anamine compound and the like for a starting material from viewpoints of areaction operation and an yield. For example, unit operations such assynthesis of thioether (sulfide) and synthesis of ester; reactions ofmercapto group with reactive functional groups such as vinyl group,halogen atoms (including haloalkyl groups), epoxy group, aziridine ring,acyl halide groups, and isocyanate group; and amination reaction,amidation reaction, alkylation reaction and the like are well known tothose skilled in the art. Therefore, it is possible to chose suitablemethods from the conventional methods considering an yield, easiness ofreaction and the like.

[0089] For example, in these production methods, when any of the definedgroups are changed under the condition of the reaction steps, orunsuitable to proceed the reaction steps, desired steps may beefficiently performed by using techniques commonly used in the syntheticorganic chemistry, for example, protection and deprotection offunctional groups, or treatments including oxidation, reduction, andhydrolysis. Isolation and purification of synthetic intermediates andtarget compounds in the aforementioned steps can be performed by commontechniques in the field of synthetic organic chemistry, for example,filtration, extraction, washing, drying, concentration,recrystallization, various chromatography methods and the like. Inaddition, synthetic intermediates may be used in subsequent stepswithout isolation.

EXAMPLES

[0090] The present invention will be more specifically explained withreference to the following examples. However, the scope of the presentinvention is not limited to these examples. The compound numbers used inthe examples correspond to the compound numbers shown in theaforementioned tables.

Example 1 Synthesis of Compound 45

[0091] Bis(2-chloroethyl)amine hydrochloride (17.8 g) andthiohydroquinone (25.2 g) were added to a 1,000 ml flask provided with astirrer and a condenser, and methanol (300 ml) was added thereto fordissolution. To this solution, a 28% solution (57.9 g) of sodiummethoxide in methanol was added dropwise at room temperature. After theaddition was completed, the reaction mixture was stirred under reflux byheating for 3 hours, and then left standing for one day. The reactionmixture was transferred to a 3 liter-beaker, 1,500 ml of water wasadded, and the deposited product was separated. The crude product wasrecrystallized from methanol to obtain 20 g of the target compound (m.p.133-134° C.).

[0092]¹H-NMR (DMSO-d₆) δ (ppm) 2.61 (t, 4H), 2.83 (t, 4H), 3.38 (s, 1H),6.72 (dd, 4H), 7.20 (dd, 4H), 9.55 (s, 2H)

Example 2 Synthesis of Compound 113

[0093] In a 100 ml three-neck flask, Compound 45 (3.2 g) synthesized inExample 1 was dissolved in dimethylacetamide (15 ml), and propionicanhydride (1.4 ml) was dropwise added thereto under ice cooling. Thereaction mixture was stirred for 1 hour at room temperature, poured intodiluted hydrochloric acid, and extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried over magnesium sulfate, andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (ethyl acetate/hexane=7/3-1/1) toobtain 3.58 g of the target compound.

[0094]¹H-NMR (DMSO-d₆) δ (ppm) 0.37 (t, 3H), 2.04 (q, 2H), 2.90 (m, 4H),3.30 (m, 4H), 6.76 (d, 4H), 7.20 (d, 4H), 9.57 (s, 1H), 9.60 (s, 1H)

Example 3 Synthesis of Compound 61

[0095] 3-Bromopropylamine hydrobromide (50.0 g) and methylene chloride(300 ml) were put into a 1,000 ml flask provided with a stirrer and acondenser, and triethylamine (46 g) was added thereto at a temperaturebelow 10° C. Then, bromoacetyl chloride (36 g) was added dropwise to themixture while keeping the temperature of the reaction mixture at 20° C.or below 20° C., and then the mixture was stirred for 1 hour. Theorganic layer was separated by filtration and concentrated, and theresidue was purified by silica gel column chromatography (developingsolvent: hexane/ethyl acetate=2:1) to obtain(3-bromopropyl)-1-bromoacetamide (yield: 24%). Thiohydroquinone (5.0 g)and (3-bromopropyl)-1-bromoacetamide (5.8 g) were added to methanol (50ml), and 28% sodium methoxide (7.6 g) was added thereto with stirringand the mixture was stirred at 40° C. for 2 hours. Water (200 ml) wasadded to the reaction mixture, the mixture was extracted with ethylacetate, and the organic phase was dried. The product obtained afterevaporation of the solvent was treated with acetonitrile to obtaincrystals (m.p. 122-124° C.).

Example 4 Synthesis of Compound 1

[0096] 2,6-Dichloromethylpyridine (3.5 g), and thiohydroquinone (5.0 g)were put into a 100 ml flask provided with a stirrer and a condenser,and methanol (20 ml) and a 28% solution (7.7 g) of sodium methoxide inmethanol were added thereto at room temperature. The mixture was warmedto 60° C., and stirred for 1 hour at the same temperature. After themethanol was evaporated, the organic phase was extracted with ethylacetate. The organic phase was dried and concentrated to obtain crystalsof the target compound. The product was recrystallized from acetonitrileto obtain the target compound (yield: 70%, m.p. 140-140.5° C.).

Example 5 Synthesis of Compound 27

[0097] Methanol (40 ml) was put into a flask provided with a stirrer,thiohydroquinone (0.08 mol) and 48% aqueous NaOH (0.084 mol) were addedthereto, and then bis-2-chloroethyl ether (0.04 mol) was dropwise addedthereto with stirring at room temperature. The mixture was maintained at40° C. for 4 hours, then added to water (300 ml) and extracted withethyl acetate. The organic phase was washed with water and dried, andthe solvent was evaporated to obtain crude crystals of the targetcompound. The crystals were recrystallized from benzene to obtain thetarget compound (yield: 82%, m.p. 91-92° C.).

Example 6 Synthesis of Compound 162

[0098] β,β′-Dichlorodiethylformal was synthesized according to themethod of Vinokurov D. M. The target compound was obtained in the samemanner as in Example 5 except that the above-obtained compound was usedas a halide starting material. The target compound was obtained throughrecrystallization from a mixed solvent of water and methanol (yield:81%, m.p. 108-110° C.)

Example 7 Synthesis of Compound 124

[0099] Compound 45 (10.0 g) obtained in Example 1 was put into a 500 mlflask provided with a stirrer and a calcium chloride tube, anddimethylacetamide (100 ml) was added thereto for dissolution. To thissolution was added triethylamine (7.78 ml) and 4-morpholinecarbonylchloride (4.17 g), the mixture was stirred for 2 hours, then water wasadded thereto and the mixture was further made neutral with hydrochloricacid. The organic layer was extracted with ethyl acetate, washed withwater (3 times) and with saturated brine (2 times), then dried andconcentrated to obtain 8.30 g of Compound 124 (semi-solid).

[0100]¹H-NMR (DMSO-d₆) δ (ppm) 2.86 (t, 4H), 2.87 (t, 4H), 3.20 (t, 4H),3.33 (t, 4H), 6.74(d, 4H), 7.23 (d, 4H), 9.61(s, 2H)

Example 8 Synthesis of Compound 97

[0101] Compound 45 (964 mg) obtained in Example 1 was put into a 20 mlflask provided with a calcium chloride tube, and dimethylformamide (5ml) was added thereto for dissolution. To this solution was added sodiumhydrogen carbonate (1 g), potassium iodide (166 mg) and chloroacetamide(300 mg), and the mixture was stirred at 80° C. for 2 hours. Thereaction mixture was added to water, the mixture was extracted withethyl acetate, and the organic layer was washed with water (3 times) andsaturated brine (2 times), then dried and concentrated. The residue waspurified by silica gel chromatography (eluent: methylene chloride/ethylacetate=213), and the solvent was concentrated. The residue wascrystallized by adding hexane, filtered, washed and dried to obtain 900mg of Compound 97 (m.p. 105-106° C.).

[0102]¹H-NMR (CD₃OD) δ (ppm) 2.72 (t, 4H), 2.82 (t, 4H), 3.10 (s, 2H),6.80 (d, 4H), 7.30 (d, 4H)

Example 9 Synthesis of Compound 190

[0103] 2-Fluorophenol (4.05 g), water (50 ml), copper sulfatepentahydrate (18.0 g), and ammonium thiocyanate (11.0 g) weresuccessively put into a 300 ml flask provided with a stirrer, and themixture was stirred for 4 hours on a water bath (50° C.). The solid wasremoved by filtration, and the filtrate was extracted with ethylacetate, then dried and concentrated. The residue was purified by silicagel chromatography (eluent: hexane/ethyl acetate=10/1.5) to obtain 1.61g of 3-fluoro-4-hydroxybenzothiocyanate.

[0104]¹H-NMR (CDCl₃)δ (ppm) 5.79 (s, 1H), 7.07 (dd, 1H), 7.28 (dd, 1H),7.36 (dd, 1H)

[0105] The resulting 3-fluoro-4-hydroxybenzothiocyanate (0.45 g) was putinto a nitrogen-purged 50 ml flask provided with a stirrer, anddissolved in tetrahydrofuran (5.0 ml). The solution was cooled to 0° C.,aluminium lithium hydride (0.10 g) was added thereto, and then themixture was stirred at room temperature for 20 minutes. To the mixturewas then added ethyl acetate and saturated aqueous ammonium chloride,and the mixture was neutralized with diluted hydrochloric acid. Theorganic layer was extracted with ethyl acetate, dried and concentrated.The residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=10/1.5) to obtain 0.13 g of3-fluoro-4-hydroxythiophenol.

[0106]¹H-NMR (CDCl₃)δ (ppm) 3.42 (s, 1H), 5.52 (s, 1H), 6.88 (dd, 1H),7.00 (dd, 1H), 7.08 (dd, 1H)

[0107] The 3-fluoro-4-hydroxythiophenol (0.13 g) obtained above was putinto a 50 ml flask provided with a stirrer, and dissolved in methanol(5.0 ml). The solution was bubbled with nitrogen gas for about 15minutes for deairing, sodium methoxide (28%, 0.20 ml) andbis(2-chloroethyl) ether (0.52 ml) were added thereto, and then themixture was stirred for 2 hours (40° C.). The mixture was neutralizedwith diluted hydrochloric acid, and the organic layer was extracted withethyl acetate, dried and concentrated. The residue was purified bysilica gel chromatography (eluent: hexanelethyl acetate=5/1) to obtain56 mg of Compound 190 (m.p. 87-88° C.). 1H-NMR (CDCl₃) δ (ppm) 2.95 (t,4H), 3.55 (t, 4H), 6.89 (dd, 1H), 7.03 (dd, 1H), 7.12 (dd, 1H)

Example 10 Synthesis of Compound 191

[0108] 5-Norbornene-2-dicarboxylic acid anhydride (1.30 g),2-(4-hydroxyphenylthio)propylamine (3.66 g), and triethylamine (2.02 g)were put into a 200 ml flask provided with a stirrer and a condenser,dimethylformamide (50 ml) was added thereto for dissolution, and thenthe solution was stirred at room temperature for 17 hours. To thereaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with 1 N hydrochloric acidand then with saturated aqueous sodium hydrogen carbonate, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (eluent:dichloromethane/ethyl acetate=2/8) to obtain 1.76 g of Compound 191 as asemi-solid substance.

[0109]¹H-NMR (DMSO-d₆) δ (ppm) 1.20 (s, 2H), 1.51 (t, 4H), 2.72 (t, 4H),2.90 (s, 2H), 2.98 (q, 4H), 3.03 (s, 2H), 6.07 (s, 2H), 6.72 (d, 4H),7.34 (d, 2H), 9.56 (s, 2H)

Example 11 Synthesis of Compound 192

[0110] 1-Cyclopentane diacetic acid (0.93 g) was put into a 100 ml flaskprovided with a stirrer and a condenser and tetrahydrofuran (35 ml) wasadded thereto for dissolution. Then, to the solution was addeddicyclohexylcarbodiimide (2.06 g) and 2-(4-hydroxyphenylthio)propylamine(1.83 g), and the mixture was stirred at 40° C. for 6 hours. Insolublematerials were removed from the reaction mixture by suction filtration,and the filtrate was concentrated under reduced pressure. The residuewas purified by silica gel chromatography (eluent: hexane/ethylacetate=1/1) to obtain 1.09 g of Compound 192 as a semi-solid substance.

[0111]¹H-NMR (DMSO-d₆) δ (ppm) 1.18 (t, 2H), 1.58 (m, 4H), 2.13 (s, 2H),2.76 (t, 2H), 3.14 (dd, 2H), 6.72 (d, 2H), 7.20 (d, 2H), 8.08 (t, 1H),9.55 (s, 1H)

Example 12 Synthesis of Compound 100

[0112] Compound 45 (1.79 g) obtained in Example 1 was put into a 50 mlflask provided with a calcium chloride tube and dimethylformamide (15ml) was added thereto for dissolution. To this solution was added sodiumhydrogen carbonate (1.68 g) and 2-chloromethylpyridine hydrochloride(820 mg), and the mixture was stirred at 70° C. for 4 hours. Thereaction mixture was added to water and the mixture was extracted withethyl acetate. The extract was washed with water (3 times) and saturatedbrine (2 times), dried, and then concentrated. The residue was purifiedby silica gel chromatography (eluent: methylene chloride/methanol=20/1),the solvent was concentrated, and the residue was crystallized by addinghexane, and then filtered to obtain 1.57 g of Compound 100 (m.p. 80-81°C.).

[0113] 1H-NMR (DMSO-d₆) δ (ppm) 2.60 (t, 4H), 2.85 (t, 4H), 3.68 (s,2H), 6.68 (d, 4H), 7.15 (d, 4H), 7.25 (t, 1H), 7.41 (d, 1H), 7.70 (t,1H), 8.42 (d, 1H), 9.55 (s, 2H)

Example 13 Synthesis of Compound 193

[0114] Compound 97 (1.00 g) obtained in Example 8 was put into a 100 mlflask provided with a calcium chloride tube at room temperature, andacetonitrile (10 ml) was added thereto for dissolution. To this solutionwas added pyridine (2.1 ml) and acetic anhydride (0.75 ml), and themixture was stirred at room temperature for 4.5 hours. The reactionmixture was concentrated under reduced pressure. The residue wasdissolved in ethyl acetate (100 ml), and then washed with 1 Nhydrochloric acid (50 ml×2). The organic layer was separated, and driedover anhydrous sodium sulfate, and then the solvent was evaporated toobtain 1.17 g of the target compound (yield: 89%, m.p. 139-142° C.).

[0115]¹H-NMR (CD₃OD) δ (ppm) 2.30 (s, 6H), 3.15-3.50 (m, 8H), 4.12 (s,2H), 7.12 (d, 4H), 7.50 (d, 4H)

Example 14 Synthesis of Compound 71

[0116] The reaction of Example 12 was repeated by using 940 mg of ethyliodide instead of 2-chloromethylpyridine hydrochloride, and the productwas purified by silica gel chromatography (eluent: methylenechloride/methanol=20/1) to obtain Compound 71 (1.49 g) as oil.

[0117]¹H-NMR (DMSO-d₆) δ (ppm) 0.89 (t, 3H), 2.48 (q, 2H), 2.60 (t, 4H),2.80 (t, 4H), 6.78 (d, 4H), 7.25 (d, 4H), 9.62 (s, 2H)

Example 15 Syntheses of Compounds 72 to 81, Compounds 84 to 88, Compound95, Compounds 102 to 103, Compounds 107 to 111, Compound 194, Compounds197 to 201, Compounds 203 to 211 and Compound 213

[0118] The title compounds were synthesized in the same manner as inExample 14 by allowing Compound 45 obtained in Example 1 to react withcorresponding alkylating agents.

Example 16 Syntheses of Compounds 89 to 91, Compounds 98 to 99, Compound101, Compounds 105 to 106 and Compound 196

[0119] The title compounds were synthesized in the same manner as inExample 12 by allowing Compound 45 obtained in Example 1 to react withcorresponding arylmethyl halides or heteroarylmethyl halides.

Example 17 Synthesis of Compound 92

[0120] Compound 92 was synthesized in accordance with the followingsynthetic scheme.

[0121] Salicyl aldehyde (12.2 g), imidazole (7.2 g), anddimethylformamide (70 ml) were put into a 200 ml three-neck flask fordissolution, tert-butyldimethylsilyl chloride (16 g) was added theretoat room temperature and the mixture was stirred at room temperature for1 hour. Then, the reaction mixture was poured into water, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over magnesium sulfate, and concentratedunder reduced pressure to obtain Compound 92A (23.5 g) as oil. Theresulting Compound 92A was used for the subsequent reaction withoutfurther purification.

[0122] Compound 92A (18.9 g) was dissolved in 120 ml of methanol, andsodium borohydride (760 mg) was added thereto. The reaction mixture wasstirred at room temperature for 1 hour, and then poured into water andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over magnesium sulfate, andconcentrated under reduced pressure to obtain Compound 92B (18.8 g) asoil. The resulting Compound 92B was used for the subsequent reactionwithout further purification.

[0123] Compound 92B (9.5 g), triethylamine (5.6 ml), andN,N-dimethylaminopyridine (500 mg) were dissolved in acetonitrile (50ml), and methanesulfonyl chloride (4.6 g) was dropwise added thereto.The reaction mixture was left standing at room temperature overnight.The produced triethylamine hydrochloride was filtered, and the filtratewas concentrated under reduced pressure. To the residue was addedhexane, and insoluble materials were removed by filtration. Then, thefiltrate was washed with aqueous citric acid, water, and then saturatedbrine, then, dried over magnesium sulfate and concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (eluent: hexane) to obtain Compound C (7.0 g) as oil.

[0124] Compound 45 (4.8 g) synthesized in Example 1 anddimethylacetamide (40 ml) were put into a 100 ml three-neck flask fordissolution, and Compound 92B (4.1 g) was added thereto. The reactionmixture was stirred at 80° C. for 1 hour, and then poured into water andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over magnesium sulfate, andconcentrated under reduced pressure. The residue was dissolved inmethylene chloride (70 ml), 10 ml of 1 M solution of tetrabutylammoniumfluoride in tetrahydrofuran was added thereto, and then the mixture wasallowed to react at room temperature for 1 hour. The reaction mixturewas poured into water, and the mixture was extracted with methylenechloride. The organic layer was washed with saturated brine, dried overmagnesium sulfate, and concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(eluent: methylene chloride/methanol=100/3) to obtain Compound 92 (4.93g) as an amorphous.

Example 18 Syntheses of Compound 93 and Compound 94

[0125] The title compounds were synthesized in the same manner as inExample 17 by allowing Compound 45 obtained in Example 1 to react withbenzyl chloride substituted with corresponding protected hydroxyl group,and then deprotecting the product.

Example 19 Syntheses of Compound 50, Compound 51 and Compound 54

[0126] The title compounds were synthesized in the same manner as inExample 2 by allowing Compound 45 obtained in Example 1 to react with acorresponding acid anhydride.

Example 20 Synthesis of Compound 53

[0127] Compound 45 (2.0 g) obtained in Example 1, formic acid (290 mg),and dicyclohexylamide (1.4 g) were stirred in a mixed solvent ofchloroform (20 ml) and dimethyl sulfoxide (20 ml) at room temperaturefor 4 hours. The reaction mixture was filtered, and the residue waswashed with ethyl acetate. Then, the filtrate and the washing filtratewere combined, and washed with water, saturated aqueous sodium hydrogencarbonate, and then saturated brine. The organic layer was dried oversodium sulfate, and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography to obtain 2.1 gof the target compound.

[0128]¹H-NMR (DMSO-d₆) δ (ppm) 2.87 (m, 2H), 2.95 (m, 2H), 3.30 (m, 2H),3.37 (m, 2H), 6.75 (d, 4H), 7.22 (d, 4H), 7.90 (s, 1H), 9.58 (broad, 2H)

Example 21 Synthesis of Compound 114

[0129] Compound 45 (9.64 mg) synthesized in Example 1, pyridine (0.25ml), and dimethylacetamide (5 ml) were added to a 30 ml three-neck flaskfor dissolution. To the solution was added dropwise benzoyl chloride(5.34 mg) under ice cooling, and the mixture was stirred for 30 minutesunder ice cooling, and then for 1 hour at room temperature. The reactionmixture was poured into diluted hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over magnesium sulfate, and then concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography (eluent: methylene chloride/methanol=10014), andcrystallized by adding hexane to obtain 510 mg of the target compound.

Example 22 Syntheses of Compound 115, Compound 116 and Compound 117

[0130] The title compounds were synthesized in the same manner as inExample 22 by allowing Compound 45 obtained in Example 1 to react with acorresponding acid chloride, and purifying the product with a silica gelcolumn.

Example 23 Synthesis of Compound 125

[0131] The title compound was synthesized in the same manner as inExample 7 by allowing Compound 45 obtained in Example 1 to react withpiperidinocarbonyl chloride.

Example 24 Synthesis of Compound 214

[0132] Compound 45 (1.29 g) obtained in Example 1 and D-mannose (1.01 g)were stirred in ethanol (5 ml) at 100° C. for 4 hours on an oil bath. Tothe reaction mixture was added ethyl acetate (50 ml), the mixture wassubjected to suction filtration, and then the filtrate was concentrated.The resulting residue was purified by silica gel column chromatography(methylene chloride/methanol=911) to obtain 1.05 g of the targetcompound.

[0133]¹H-NMR (DMSO-d6) δ (ppm) 2.73 (m, 4H), 2.83 (m, 4H), 3.55-3.80 (m,3H), 4.30-4.50 (m, 3H), 5.13 (s, 1H), 6.76 (d, 4H), 7.22 (d, 4H), 9.55(s, 2H)

Example 25 Syntheses of Compounds 215 to 219

[0134] The title compounds were synthesized in the same manner as inExample 24 by allowing Compound 45 obtained in Example 1 to react with acorresponding saccharide.

Example 26 Synthesis of Compound 59

[0135] Compound 45 (500 mg) obtained in Example 1,N-{2-(p-toluenesulfonyloxy)ethyl}phthalimide (537 mg), potassium iodide(258 mg), and sodium hydrogen carbonate (131 mg) were stirred indimethylformamide (8 ml) at 150° C. for 28 hours. The reaction mixturewas extracted with ethyl acetate, and the organic layer was washed withsaturated aqueous sodium hydrogen carbonate, dried over magnesiumsulfate, and concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography to obtain 260 mg ofphthalimide compound.

[0136] The above phthalimide compound (260 mg) and hydrazine monohydrate(31.58 mg) were stirred in ethanol (3 ml) with heating for 3 hours. Thereaction mixture was extracted with ethyl acetate, and the organic layerwas washed with saturated aqueous sodium hydrogen carbonate, dried overmagnesium sulfate, and concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(chloroform/methanol=1/1) to obtain 97 mg of the target compound.

[0137]¹H-NMR (DMSO-d₆) δ (ppm) 2.10 (m, 2H), 2.50-3.00 (m, 10H), 6.87(d, 4H), 7.27 (d, 4H)

Example 27 Syntheses of Compounds 82 to 83, Compound 195 and Compound202

[0138] The title compounds were synthesized by allowing Compound 59obtained in Example 26 to react with sodium isocyanate, aceticanhydride, methanesulfonyl chloride and3,5-dimethylpyrazole-1-carboxyamidine nitrate, respectively.

Example 28 Synthesis of Compound 48

[0139] 4-(2-Bromoethylthio)phenol (1.2 g) was dissolved indimethylformamide (10 ml) under nitrogen atmosphere, to this solutionwas added imidazole (1.5 g) and tert-butyldimethylsilyl chloride (2.45g), and the mixture was stirred at room temperature for one and a halfhours. To the reaction mixture was added water, the mixture wasextracted with chloroform, and then the organic layer was dried oversodium sulfate, and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography to obtain 1.4 gof silyl compound.

[0140] The above silyl compound (1.4 g) and hydroxylamine hydrochloride(150 mg) were mixed in ethanol (10 ml), sodium carbonate (400 mg) wasadded thereto, and the mixture was refluxed by heating for 8 hours. Thereaction mixture was filtered, and the residue obtained by concentratingthe filtrate under reduced pressure was purified by silica gel columnchromatography (ethyl acetate/hexane=1/4) to obtain 506 mg ofhydroxylamine compound.

[0141] The above hydroxylamine compound (480 mg) was dissolved inchloroform (10 ml), to the solution was added a solution oftetrabutylammonium fluoride in tetrahydrofuran (1 equivalent) and themixture was stirred at room temperature for 20 minutes. The reactionmixture was concentrated under reduced pressure, and the resultingresidue was purified by silica gel column chromatography, andrecrystallized from a chloroform-hexane mixed solvent to obtain 320 mgof the target compound.

[0142]¹H-NMR (DMSO-d₆) δ (ppm) 2.85 (m, 6H), 3.00 (m, 2H), 6.77 (d, 4H),7.22 (d, 4H), 8.98 (broad, 2H)

Example 29 Synthesis of Compound 49

[0143] Compounds 45 (200 mg) synthesized in Example 1 and3,5-dimethylpyrazole-1-carboxyamidine nitrate (125 mg) were dissolved indimethyl sulfoxide (4 ml). To this solution was added triethylamine (1.5ml) and the mixture was stirred at 120° C. by heating for 4 hours. Thereaction mixture was extracted with ethyl acetate, and the organic layerwas washed with saturated aqueous sodium hydrogen carbonate, dried overmagnesium sulfate, and concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(ethyl acetate/methanol=95/5) to obtain 30 mg of the target compound.

[0144]¹H-NMR (DMSO-d₆) δ (ppm) 2.33 (s, 3H), 2.72 (m, 4H), 3.13 (m, 4H),6.53 (d, 4H), 7.03 (d, 4H), 9.42 (s, 2H)

Example 30 Synthesis of Compound 52

[0145] In a 100 ml three-neck flask, thiohydroquinone (1.6 g) wasdissolved in methanol (15 ml) under nitrogen atmosphere. To thissolution was added an aqueous solution (0.7 ml) of sodium hydroxide(0.51 g), N,N-bis(2-chloroethyl)-2-chloropropionamide (1.0 g) wasfurther added, and the mixture was stirred at 50° C. for 2 hours. To thereaction mixture was added ethyl acetate and diluted hydrochloric acidfor separation. The organic layer was washed with saturated brine, driedover sodium sulfate, and concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(ethyl acetate/hexane=3/2). The resulting oil was dissolved in methanol,water was added thereto, and then the precipitates produced werecollected by filtration, and dried under reduced pressure to obtain 1.2g of the target compound.

[0146]¹H-NMR (DMSO-d₆) δ (ppm) 2.32 (t, 2H), 2.86 (m, 6H), 3.32 (m, 4H),6.70 (d, 6H), 7.22 (m, 6H), 9.60 (s, 3H)

Example 31 Synthesis of Compound 212

[0147] Compound 71 (0.51 g) synthesized in Example 14 andp-toluenesulfonic acid methyl ester (0.41 g) were stirred at 120° C. for5 hours on an oil bath. To the reaction mixture was added ethyl acetateand acetone, the mixture was decanted, then to the residue was added asolution of potassium iodide (0.35 g) in acetone-methanol mixed solvent,and the mixture was subjected to suction filtration. The residueobtained by concentrating the filtrate under reduced pressure waspurified by silica gel column chromatography (methylenechloride/methanol=9/1-8/2), and the resulting oil was crystallized bytreatment with diethyl ether. The crystals were collected by filtration,and dried under reduced pressure to obtain 168 mg of the targetcompound.

[0148]¹H-NMR (DMSO-d₆) δ (ppm) 1.00 (t, 3H), 2.97 (s, 3H), 3.0-3.5 (m,10H), 6.80 (d, 4H), 7.32 (d, 4H), 9.80 (s, 2H)

Example 32 Syntheses of Compounds 220 to 223

[0149] The title compounds were synthesized by carrying out theesterification in the same manner as in Example 13.

Example 33 Syntheses of Compound 224 and Compound 225

[0150] To a solution of Compound 97 (1.0 g) synthesized in Example 8 inacetone (10 ml) were added maleic acid (0.31 g), and further ethylacetate. The resulting precipitates were separated by filtration, washedwith ethyl acetate, and dried under reduced pressure to obtain 1.25 g ofthe target compound.

[0151]¹H-NMR (CD₃OD) δ (ppm) 2.95 (m, 4H), 3.07 (m, 4H), 3.63 (s, 2H),6.28 (s, 2H), 6.76 (d, 4H), 7.27 (d, 4H)

[0152] In a similar manner, Compound 225 was obtained by using citricacid.

Example 34 Synthesis of Compound 226

[0153] Thiohydroquinone (5.05 g), 28% solution of sodium methoxide(8.2g) in methanol, and methanol (30 ml) were mixed under water cooling.To the resulting solution was added a solution of1,4-bis(5-bromopentanoyl)piperazine (8.8 g) in methanol (10 ml), and themixture was stirred at 40° C. for 2 hours. The reaction mixture wascooled to room temperature, and concentrated under reduced pressure. Theresulting residue was dissolved in ethyl acetate (200 ml), and washedwith saturated brine (×2). The precipitates produced were separated byfiltration, and dried under reduced pressure to obtain 9.00 g of thetarget compound.

[0154]¹H-NMR (DMSO-d₆) δ (ppm) 1.30-1.60 (m, 12H), 2.27 (t, 4H), 2.74(t, 4H), 3.25-3.46 (m, 8H), 6.72 (d, 4H), 7.18 (d, 4H), 9.53 (s, 2H)

Example 35 Synthesis of Compound 227

[0155] Thiohydroquinone (4.0 g) was dissolved in methanol (20 ml). Tothis solution was added a 28% solution of sodium methoxide (6.7 g) inmethanol, the mixture was stirred, a solution of1,4-bis(2-chloropropionyl)piperazine (3.8 g) in methanol (20 ml) wasfurther added thereto, and the mixture was refluxed by heating for 4hours. The reaction mixture was cooled to room temperature, dilutedhydrochloric acid was added thereto, and the mixture was extracted withethyl acetate. The organic layer was washed with water, and theresulting precipitates were separated by filtration, and washed withethyl acetate. These crystals were dried under reduced pressure toobtain 6.0 g of the target compound.

[0156]¹H-NMR (DMSO-d₆) δ (ppm) 2.60 (t, 4H), 2.96 (t, 4H), 3.28-3.56 (m,8H), 6.76 (d, 4H), 7.23 (d, 4H), 9.62 (s, 2H)

Example 36 Synthesis of Compound 228

[0157] The title compound was synthesized in the same manner as inExample 35.

[0158] The results of mass spectroscopy (Fast Atom Bombardment MassSpectroscopy, positive, p-Nitrobenzylalcohol) are described below. TABLE5 Compound No. Parent peak  45 322  48 338  49 364  50 392  51 422  52502  53 350  54 364  57 481  58 495  59 365  71 350  72 364  73 360  74362  75 376  77 361  78 393  79 421  80 449  81 378  82 408  83 407  84368  85 404  86 447  87 396  88 408  89 418  90 402  91 413  92 428  93428  94 428  95 380  97 379  98 412  99 413 100 413 101 463 102 366 105430 106 430 107 463 108 461 109 421 110 435 111 433 113 378 114 426 116427 118 400 124 435 125 433 191 485 192 517 193 464 194 436 195 443 196402 197 468 198 424 199 410 200 436 201 396 202 407 203 447 204 485 205453 206 463 207 423 208 467 209 490 210 462 211 457 212 364 213 463 214484 215 484 216 484 217 494 218 483 219 497 220 524 221 767 222 521 223721 224 379 225 379

Text Example 1 Test of measurement of RNR inhibitory activity

[0159] (a) Preparation of R1 and R2 subunits of human RNR

[0160] Starting from a plasmid p3I containing CDNA coding for R1 subunitof human RNR protein (disclosed in Nucleic Asids Research, 19, p.3741,1991), a DNA was obtained, in which was introduced an Nde I restrictionsite just before the translation initiation site of R1 subunit and a BamHI restriction site just after the translation termination site in sucha manner that the amino acid sequence of R1 subunit was completelyunchanged. The preparation of DNA was carried out by methods ofintroducing mutations and DNA amplification based on the PCR utilizingsynthetic DNA fragments according to the method described in theMolecular Cloning, 2nd Edition. The Nde I/Bam HI restriction fragmentcontaining a region coding for the R1 subunit deriving from the DNA wasinserted between the NdeI and Bam HI sites of plasmid pET3a (Novagen) toconstruct a plasmid pETRI. The plasmid was transformed into Eschelichiacoli BL21(λ DE3)plysS strain (Novagen) to construct a BL21(λDE3)plysSpETR1 strain also according to the method described in theMolecular Cloning, 2nd Edition.

[0161] Similarly, a DNA fragment was obtained, from a human cell strainHL60 cDNA library through the methods of introducing mutations and DNAamplification based on the PCR utilizing synthetic DNA fragments, whichwas introduced with an Nde I restriction site just before thetranslation initiation site of R² subunit and a Bam HI restriction sitejust after the translation termination site in such a manner that theamino acid sequence of R2 subunit were completely unchanged. The NdeI/Bam HI restriction fragment containing the region coding for the R2subunit deriving from the DNA was inserted between the NdeI and Bam HIsites of plasmid pEt3a (Novagen) to construct a plasmid pETR2. Thisplasmid was transformed into Eschelichia coli BL21(λ DE3)plysS strain(Novagen) also according to the method described in the MolecularCloning, 2nd Edition to construct a BL21(λ DE3)plysSpETR2 strain.

[0162] By using one loop, the BL21(λ DE3) plysSpETRl strain wasinoculated to 40 ml of Terrific Broth (containing 100 μg/ml ofampicillin and 20 μg/ml of chloramphenicol and free from glycerol,described in Molecular Cloning, 2nd Edition) contained in a 300 mlErlenmeyer flask, and cultured at 28° C. overnight with shaking. 30 mlof the culture broth was inoculated in 400 ml of the same culture brothcontained in a 2 liter Erlenmeyer flask, and cultivation was carried outat 16° C. with shaking. Two hours after the start of the cultivation,IPTG was added to the broth to a final concentration of 0.1 mM, and thenthe cultivation was continued for 20 hours. Cells were collected fromthe culture broth by centrifugation at 7,000× g for 10 minutes at 4° C.,and the cells collected were suspended in 20 ml of Buffer A [50 mMHEPES-NaOH (pH 7.6), 1 mM MgCl₂, 1 mM dithiothreitol, 1 mM PMSF] cooledwith ice. This suspension was sonicated to disrupt the cells, and thencentrifuged at 12,000× g for 20 minutes at 4° C. The supernatant wascollected, streptomycin sulfate was added thereto to a finalconcentration of 2% (W/V) and the mixture was maintained on ice for 20minutes, and then centrifuged at 12,000× g for 20 minutes at 4° C. Thesupernatant was collected, an equal volume of 100% saturated aqueousammonium sulfate was added thereto with stirring, and then the mixturewas maintained on ice overnight. Precipitates were collected bycentrifugation at 15,000× g for 20 minutes at 4° C. and dissolved in 2ml of Buffer A, and then the solution was subjected to desalting andbuffer substitution with Buffer A by using PD-10 (Pharmacia Biotech) ina conventional manner.

[0163] For all of the subsequent separation and purification steps, FPLCSystem (Pharmacia Biotech) was used. The desalted fraction was appliedto Q-Sepharose FF (Pharmacia Biotech), and separation was carried outunder the following conditions: flow rate: 5.0 ml/minute, separationtime: 50 minutes, eluent: 0 M to 0.5 M KCl linear gradient in 10 mMpotassium phosphate buffer (pH 7.0). The fractions eluted from 10minutes to 20 minutes were collected and ammonium sulfate was addedthereto to a final concentration of 0.5 M. The fractions were applied toPhenyl Sepharose HP (Pharmacia Biotech) and eluted at a flow rate of 3.0ml/minute with 10 mM potassium phosphate buffer (pH 7.0)/0.5 M ammoniumsulfate for 15 minutes, with 10 mM potassium phosphate buffer (pH 7.0)for 15 minutes, and then with 10 mM potassium phosphate buffer (pH7.0)/0.3% Tween 20 for 15 minutes. The fractions eluted in the last 15minutes were collected and applied to Resource Q 1 ml (PharmaciaBiotech), washed with 10 mM potassium phosphate buffer (pH 7.0), andeluted at a flow rate of 1 ml/minute with 10 mM potassium phosphatebuffer (pH 7.0)/0.3 M KCl for 10 minutes. The fractions eluted in thefirst 3 minutes were collected, and subjected to desalting and buffersubstitution with Buffer A by using PD-10 to obtain a purified R1preparation.

[0164] By using one loop, the BL21(λ DE3) plysSpETR² strain wasinoculated to 40 ml of Terrific Broth (containing 100 μg/ml ofampicillin and 20 μg/ml of chloramphenicol and free from glycerol,described in Molecular Cloning, 2nd Edition) in a 300 ml Erlenmeyerflask, and cultured at 28° C. overnight with shaking. 30 ml of theculture broth was inoculated to 400 ml of the same culture broth in a 2liter Erlenmeyer flask, and then the cultivation was carried out at 28°C. with shaking. When O.D. (600 nm) reached around 0.8, IPTG was addedto the broth to a final concentration of 1 mM, and the cultivation wascontinued for 6 hours. Cells were collected from the culture broth bycentrifugation at 7,000 X g for 10 minutes at 4° C., and the cellsobtained were suspended in 20 ml of Buffer A cooled with ice. Thissuspension was sonicated to disrupt the cells, and then centrifuged at12,000× g for 20 minutes at 4° C. The supernatant was collected,streptomycin sulfate was added thereto to a final concentration of 2%(W/V), and the mixture was maintained on ice for 20 minutes, and thencentrifuged at 12,000× g for 20 minutes at 4° C. The supernatant wascollected, an equal volume of 100% saturated aqueous ammonium sulfatewas added thereto with stirring, and then the mixture was maintained onice overnight. Precipitates were collected by centrifugation at 15,000×for 20 minutes at 4° C. and dissolved in 2 ml of Buffer A, and then thesolution was subjected to desalting and buffer substitution with BufferA by using PD-10 (Pharmacia Biotech) in a conventional manner.

[0165] For all of the subsequent separation and purification steps, FPLCSystem (Pharmacia Biotech) was used. The desalted fraction was appliedto Q-Sepharose FF (Pharmacia Biotech), and separation was carried outunder the following conditions: flow rate: 5.0 ml/minute, separationtime: 50 minutes, eluent: 0 M to 0.5 M KCl linear gradient in 10 mMpotassium phosphate buffer (pH 7.0). The fractions eluted from 10minutes to 25 minutes were collected, ammonium sulfate was added theretoto a final concentration of 0.5 M, and the mixture was applied toResource ETH. The fractions were eluted at a flow rate of 0.5 ml/minutewith 10 mM potassium phosphate buffer (pH 7.0)/0.5 M ammonium sulfatefor 15 minutes, with 10 mM potassium phosphate buffer (pH 7.0) for 15minutes, and then with 10 mM potassium phosphate buffer (pH 7.0)/0.3%Tween 20 for 15 minutes. The fractions eluted in the last 15 minuteswere collected and applied to Resource Q 1 ml (Pharmacia Biotech), andthen washed with 10 mM potassium phosphate buffer (pH 7.0)/0.5 Mammonium sulfate at a flow rate of 1 ml/minute for 10 minutes. Thefractions were eluted with 10 mM potassium phosphate buffer for 10minutes. The fractions eluted in the first 3 minutes were collected, andsubjected to desalting and buffer substitution with Buffer A by usingPD-10 to obtain a purified R² preparation.

[0166] (b) In vitro Measurement of Human RNR Inhibitory Activity

[0167] By using the above-obtained human RNR subunits, inhibitoryactivity on the human RNR was tested in vitro. The composition of thereaction mixture is as follows:

[0168] 50 mM HEPES-NaOH (pH 7.6)

[0169] 5 mM MgCl2

[0170] 10 mM Dithiothreitol

[0171] 100 μM CDP

[0172] 1 mM ATP

[0173] 40 ng/ml Purified human RNR R1 subunit, and

[0174] 40 ng/ml Purified human RNR R2 subunit.

[0175] The above reaction mixture (25 μl) containing a test compound atan appropriate final concentration was prepared, and the conversion fromCDP to dCDP by RNR was carried out at 37° C. for 30 minutes. Thereaction mixture was subjected to a heat treatment at 95° C. for 5minutes, and centrifuged at 10,000× g for 5 minutes at 4° C. 20 μl ofthe supernatant was collected and 5 μl of 25 mg/ml snake venom (Sigma)was added thereto. Dephosphorylation reaction was carried out at 37° C.for 60 minutes to allow complete conversion of CDP, ATP and dCDP as thereaction product present in the reaction mixture into CR, AR and CdR,respectively. The reaction mixture was subjected to a heat treatment at95° C. for 5 minutes, and centrifuged at 10,000× g for 5 minutes at 4°C. 180 μl of acetonitrile was added to 20 μl of the supernatant, and themixture was centrifuged again at 10,000× g for 5 minutes at 4° C., andthe resulting supernatant was used as a sample for analysis. Theanalysis was performed by high performance liquid chromatography.Analytical conditions are as follows:

[0176] Column: Licrospher NH2 (Merck)

[0177] Flow rate: 1.5 ml/min

[0178] Detection: 270 nm, and

[0179] Eluent: acetonitrile/water (90:10, VIV).

[0180] CdR in the analyzed sample was identified and its concentrationwas determined by comparison with elution time and peak area with thoseof CdR at known concentration. A concentration of a test compound whichinhibited the RNR activity by 50% under the aforementioned conditionswas calculated by comparing a CdR concentration in a sample, obtainedfrom the reaction without drug treatment, with a CdR concentration in asample obtained from the reaction wherein the test compound at a knownconcentration was added, and the value obtained was determined as IC₅₀.

Test Example 2 Test for growth inhibition of Hela S3 Cells

[0181] HeLa S3 cells prepared at 1×10⁴ cells/ml in MEM culture mediumcontaining 10% fetal bovine serum and 2 mM glutamine were added to eachwell of a 96-well microtiter plate (0.1 ml for each well). The cellswere cultured at 37° C. in a CO₂ incubator for 24 hours, and then 0.05ml of test compound appropriately diluted with the above medium wasadded to each well, and then the mixture was cultured at 37° C. in a CO₂incubator for 72 hours. After the culture supernatant was removed, eachwell was washed with 0.1 ml of PBS buffer twice, and 0.1 ml of theaforementioned medium was added to each well again.

[0182] Cell Proliferation Kit II (Boehringer Mennheim) was used formeasurement of cell number in each well. After a coloring reactionreagent was added, the plate was warmed to 37° C. in a CO₂ incubator for3 hours. Then, absorbances at 490 nm and 655 nm were measured by amicroplate reader, and a value (difference of absorbance) was calculatedfor each well by subtracting the absorbance at 650 nm from theabsorbance at 490 nm. By comparing the differences of absorbance forcells without treatment and cells treated with a test compound at aknown concentration, a concentration of test compound which inhibitedthe cell growth by 50% was calculated, and the value obtained wasdetermined as IC₅o. The values of RNR inhibitory activity obtained inExample 8, and the values of cell growth inhibitory activity obtained inExample 9 are shown in the following tables (the compound numbers usedin the tables correspond to the compound numbers shown in theaforementioned tables). TABLE 6 RNR Inhibition Cell growth inhibitionCompound No. (IC₅₀, μM) (IC₅₀, μM) 1 4.26 5.15 7 4.82 >101 8 4.38 6.5027 0.50 1.53 45 3.64 5.64 48 1.73 5.16 49 5.45 16.04 50 3.97 3.81 524.38 6.50 53 1.05 1.71 54 0.48 4.63 55 6.87 7.78 57 0.73 14.44 58 4.7618.59 59 5.73 5.81 60 2.75 7.67 61 3.77 13.40 71 1.23 3.94 72 1.19 2.1873 0.60 1.61 74 0.82 2.00 75 1.66 3.56 77 0.06 2.38 78 0.31 1.61 79 1.373.06 80 0.74 1.43 81 0.29 1.23 82 1.42 1.30 83 2.95 5.17 84 2.74 11.9985 0.61 2.50 86 3.14 3.78 87 1.01 2.57 88 1.79 3.22 89 1.46 4.66 90 2.036.38 91 1.69 2.72 92 0.89 2.14 93 0.63 9.04 94 0.46 4.00 95 0.88 3.56 970.17 0.88 98 3.36 14.97 99 2.79 5.80 100 1.58 4.97 101 5.05 12.88 1020.69 1.42 103 2.11 1.74 104 2.11 1.74 105 3.99 9.07 106 4.64 6.77 1074.20 24.86 108 0.64 2.64 109 2.36 38.89 111 1.85 11.39 113 4.77 3.80 1143.44 2.74 115 4.14 6.14 116 4.13 3.02 117 1.69 2.72 118 6.87 7.78 1240.09 3.68 125 0.91 4.55 131 6.59 127.70 132 3.50 45.55 133 2.27 14.51134 0.68 2.05 135 0.43 6.02 136 0.69 9.14 137 0.87 5.45 138 2.29 18.28152 5.14 17.96 156 2.27 5.45 158 1.42 12.72 159 0.69 6.89 160 0.95 20.09161 1.13 34.19 162 1.70 3.70 163 2.10 5.17 165 3.98 50.14 166 3.09 31.25171 8.01 30.03 172 2.64 19.48 173 3.63 12.93 183 0.42 10.42 184 0.302.46 186 11.93 56.03 190 1.38 16.86 191 1.36 4.78 192 2.85 4.51 193 N.T.0.36 194 0.84 11.71 195 0.55 3.16 196 1.52 7.08 197 3.24 4.06 198 4.864.85 199 3.99 5.14 200 4.20 4.13 201 2.49 4.29 202 1.87 42.64 203 3.183.45 204 1.50 3.38 205 1.19 7.32 206 1.13 3.31 207 0.87 1.71 208 3.465.93 209 2.67 3.09 210 5.91 2.82 211 3.24 3.04 213 2.06 179.95 214 2.697.73 215 3.68 12.72 216 3.63 11.54 218 4.97 23.18 219 3.51 25.20 2205.20 0.29 222 0.43 0.36 224 0.42 0.40 225 0.63 0.55

Test Example 3 Antineoplastic Effect Against Human Ovary Cancer A2780Cells

[0183] 2 mm cubes (tumor fragments of 8 mm3) of human ovary cancer A2780cells were subcutaneously transplanted to nude mice BALB/cAJcl-nu (CLEAJAPAN) in the abdomens. When the tumor volume reached to from 50 to 300mm³ after the transplantation, the mice were arbitrarily divided intogroups each consisting of 5 mice, and intraperitoneally administeredwith a drug solution once a day for 5 days. After weighing compounds,the drug solution was prepared before use by dissolving the drug in99.5% ethanol (final concentration: 5%, analytical grade, Kanto Kagaku)or N,N-dimethylacetamide (final concentration: 5%, analytical grade,Kanto Kagaku), adding CREMOPHOR EL (a derivative of caster oil andethylene oxide, final concentration: 10%, Sigma Chemical) to thesolution, and suspending the solution in physiological saline (OtsukaPhysiological Saline for Injection, Otsuka Pharmaceutical). Forevaluation of the effect, a tumor volume was calculated in accordancewith Equation 1, a ratio of tumor volume (V) after the administration ofdrug solution to tumor volume (Vo) before the administration of drugsolution was calculation (V/Vo), and the ratio was compared with thatfor the untreated group to determine T/C (Equation 2). The results areshown in the table set out below. In the table, administration dose, T/Cand evaluation day are shown. Equation  1 : Tumor  volume  (mm³)Equation2 : T/C = (V/V₀  for  drug-administered  group)/(V/V₀  for  untreated  group)

TABLE 7 Compound Dose Antitumor Evaluation No. mg/kg/day activity T/Cday* 27 500 0.46 7 48 500 0.54 7 72 500 0.50 4 77 500 0.54 4 78 500 0.534 79 500 0.40 4 91 500 0.48 4 94 500 0.53 7 97 500 0.43 7 102 500 0.47 7103 500 0.50 4 193 250 0.46 4 209 500 0.50 7 211 500 0.37 9 177 500 0.544 227 500 0.53 7

Test Example 4 Antineoplastic Effect Against Human Lung Cancer Lu-65Cells

[0184] 2 mm cubes (tumor fragments of 8 mm3) of human lung cancer Lu-65cells were subcutaneously transplanted to nude mice BALB/cAJcl-nu (CLEAJAPAN) on their abdomens. When the tumor volume reached to from 50 to300 mm³ after the transplantation, the mice were arbitrarily dividedinto groups each consisting of 5 mice, and intraperitoneallyadministered with a drug solution twice a day for 5 days. After weighingcompounds, the drug solution was prepared before use by dissolving thedrug in 99.5% ethanol (final concentration: 5%, analytical grade, KantoKagaku), adding CREMOPHOR EL (a derivative of caster oil and ethyleneoxide, final concentration: 10%, Sigma Chemical) to the solution, andsuspending the solution in physiological saline (Otsuka PhysiologicalSaline for Injection, Otsuka Pharmaceutical). For evaluation of theeffect, a tumor volume was calculated in accordance with Equation 1, aratio of tumor volume (V) after the administration of drug solution totumor volume (V₀) before the administration of drug solution wascalculated (V/V₀), and the ratio was compared with that for theuntreated group to determine T/C (Equation 2). The results are shown inthe table set out below. Equation  1 : Tumor  volume  (mm³)Equation2 : T/C = (V/V₀  for  drug-administered  group)/(V/V₀  for  untreated  group)

TABLE 8 Compound Dose Antitumor Evaluation No. mg/kg/day activity T/Cday* 27 1000 (500 × 2) 0.25 7

[0185] Industrial Availability

[0186] The compounds of the aforementioned formula (I) or (II), whichare the active ingredient of the medicament of the present invention,can inhibit ribonucleotide reductase, and selectively inhibitproliferation of cancer cells. Therefore, the medicament of the presentinvention is useful, for example, as an agent for cancer treatment. Thenovel compounds represented by the aforementioned formula (XII) providedby the present invention are useful as active ingredients of medicamentssuch as medicaments for cancer treatment.

What is claimed is:
 1. A medicament for treatment of cancer comprising acompound represented by the following general formula (I) or aphysiologically acceptable salt thereof: Ar¹—S—R¹—S—Ar² wherein R¹represents a nonmetal bridging group; Ar¹ and Ar² independentlyrepresent a group selected from the group consisting of an aryl groupwhich has, on its ring, one to three hydroxyl groups optionallysubstituted with a monovalent group and said aryl group may have one tothree substituents other than hydroxyl group on its ring; and aheteroaryl group which has, on its ring, one to three hydroxyl groupsoptionally substituted with a monovalent group and said heteroaryl groupmay have one to three substituents other than hydroxyl group on itsring.
 2. The medicament for treatment of cancer according to claim 1comprising a compound or a physiologically acceptable salt thereof,wherein RI is represented by the general formula (II):—R²—N(R⁴)—R³—  (II) wherein R² and R³ independently represent a divalentgroup; R⁴ represents a monovalent group; and R⁴ may bind to R² or R³ toform a cyclic structure which may further bind to one or two C₁₋₄alkylene groups to form a divalent group.
 3. The medicament fortreatment of cancer according to claim 1 comprising a compound or aphysiologically acceptable salt thereof, wherein R¹ is represented bythe general formula (III): —R⁵—X¹—R⁶—  (III) wherein R⁵ and R⁶independently represent a single bond or a divalent group not containinga nitrogen atom; X¹ represents an oxygen atom, S(O)_(k) wherein krepresents an integer of from 0 to 2, or[(R⁹X²)_(m)(R¹⁰X³)_(n)(R¹¹X⁴)_(p)]_(q) wherein R⁹, R¹⁰ and R¹¹independently represent a single bond or a divalent group not containinga nitrogen atom, and any groups selected from R⁵, R⁶, R⁹, R¹⁰ and R¹¹may bind together to form a cyclic structure, X², X³ and X⁴independently represent an oxygen atom, S(O)r wherein r represents aninteger of from 0 to 2, or a single bond, and m, n, p and qindependently represent an integer of from 1 to
 3. 4. The medicament fortreatment of cancer according to claim 1 comprising a compound or aphysiologically acceptable salt thereof, wherein R¹ is2,6-pyridinediyldimethyl group wherein the pyridinediyldimethyl groupmay have one to three substituents other than hydrogen atom on its ring.5. The medicament for treatment of cancer according to claim 2comprising a compound or a physiologically acceptable salt thereof,wherein R² and R³ are the same divalent groups; and R⁴ is a C₁₋₄ alkylgroup which may have one to three substituents other than hydrogen atom.6. The medicament for treatment of cancer according to claim 2comprising a compound or a physiologically acceptable salt thereof,wherein R² and R³ are the same divalent groups; R⁴ is represented byCOR²⁵ wherein R²⁵ represents hydrogen atom, a C₁₋₄ alkyl group, an arylgroup, a heteroaryl group, a heterocyclic group, an aralkyl group, orNR²⁶R²⁷ wherein R²⁶ and R²⁷ each represent hydrogen atom, a C₁₋₄ alkylgroup, an aryl group, a heteroaryl group, a heterocyclic group, or anaralkyl group, and said alkyl group, aryl group, heteroaryl group,heterocyclic group, and aralkyl group including those for R²⁶ and R²⁷may have one to three substituents other than hydrogen atom.
 7. Themedicament for treatment of cancer according to claim 1 comprising acompound or a physiologically acceptable salt thereof, wherein R¹ isrepresented by R^(1A)-R^(1B)CO-R^(1C)-R^(1D)-R^(1C)-COR^(1B)-R^(1A)wherein R^(1A) represents a C₁₋₄ lower alkylene group; R^(1B) representsNH or methylene group; R^(1C) represents a single bond or methylenegroup; R^(1D) represents a divalent bridging cyclic hydrocarbon group,monocyclic hydrocarbon group, or heterocyclic group, and said bridgingcyclic hydrocarbon group, monocyclic hydrocarbon group, or heterocyclicgroup may have one to three substituents other than hydrogen atom. 8.The medicament for treatment of cancer according to any one of claims 1to 7 comprising a compound or a physiologically acceptable salt thereof,wherein Ar¹ and Ar² independently represent the aryl group.
 9. Themedicament for treatment of cancer according to claim 8 comprising acompound or a physiologically acceptable salt thereof, wherein both ofAr¹ and Ar² are 4-hydroxyphenyl groups.
 10. The medicament for treatmentof cancer according to claim 8 or claim 9 comprising a compound or aphysiologically acceptable salt thereof, wherein R² and R³ are the samegroups, and the minimum number of bridge-forming atoms of R² and R³ arefrom 1 to
 10. 11. The medicament for treatment of cancer according toclaim 10 comprising a compound or a physiologically acceptable saltthereof, wherein R² and R³ are the same groups, and the minimum numberof bridge-forming atoms of R² and R³ are from 1 to
 4. 12. The medicamentfor treatment of cancer according to claim 10 or claim 11 comprising acompound or a physiologically acceptable salt thereof, wherein R² and R³are the same linear or branched divalent groups which may contain one tothree oxygen atoms.
 13. The medicament for treatment of cancer accordingto any one of claims 1 to 12 comprising a compound or a physiologicallyacceptable salt thereof, wherein the total number of carbon atoms is 35or less.
 14. The medicament for treatment of cancer according to any oneof claims 1 to 12, which is in the form of a pharmaceutical compositioncomprising the compound according to any one of claims 1 to 13 or aphysiologically acceptable salt thereof as an active ingredient togetherwith one or more pharmaceutical additives.
 15. Use of the compoundaccording to any one of claims 1 to 13 or a salt thereof for themanufacture of the medicament for treatment of cancer according to anyone of claims 1 to
 14. 16. A ribonucleotide reductase inhibitor whichcomprises the compound according to any one of claims 1 to 13 or a saltthereof.
 17. The medicament for treatment of cancer according to any oneof claims 1 to 14, which is used for preventive and/or therapeutictreatment of a disease caused by over-expression of ribonucleotidereductase.
 18. A selective cancer cell proliferation inhibitor whichcomprises the compound according to any one of claims 1 to 13 or a saltthereof.
 19. A method for treatment of a cancer which comprises the stepof administering a therapeutically effective amount of the compoundaccording to any one of claims 1 to 13 or a salt thereof to a patient.20. A compound represented by the general formula (XII) or a saltthereof: Ar²³—S—R²²—N(R²⁴)—R²³—S—Ar²⁴ wherein R² ² and R²³ independentlyrepresent a divalent group; R²⁴ represents a monovalent group or amonovalent atom; R²⁴ may bind to R²² and/or R²³ to form a cyclicstructure, which may further bind to one or two C₁₋₄ alkylene groups toform a divalent group; Ar²³ and Ar²⁴ independently represent a groupselected from the group consisting of an aryl group which has, on itsring, one to three hydroxyl groups optionally substituted with amonovalent group and said aryl group may have one to three substituentsother than hydroxyl group on its ring, and a heteroaryl group which has,on its ring, one to three hydroxyl groups optionally substituted with amonovalent group and said heteroaryl group may have one to threesubstituents other than hydroxyl group on its ring, provided thatR²²—N(R²⁴)—R²³ except for the part of R²⁴ does not contain an amide bondwhen R²² and R²³ do not form a ring, and provided that when Ar²³ andAr²⁴ is independently a phenyl group having one hydroxyl group on thering, not all of said phenyl groups have a tertiary alkyl group at aposition on the ring adjacent to the hydroxyl group.
 21. The compound orthe salt thereof according to claim 20, wherein two or three groupsselected from the group consisting of R²², R²³ and R²⁴ form a ring. 22.The compound or the salt thereof, wherein R²² and R²³ are the samedivalent groups; and R²⁴ is a C₁₋₄ alkyl group which may have one tothree substituents other than hydrogen atom.
 23. The compound or thesalt thereof, wherein R²² and R²³ are the same divalent groups; R²⁴ isrepresented by COR¹²⁵ wherein R¹²⁵ represents hydrogen atom, a C₁₋₄alkyl group, an aryl group, a heteroaryl group, a heterocyclic group, anaralkyl group, or NR¹²⁶R¹²⁷ wherein R¹²⁶ and R¹²⁷ each representhydrogen atom, a C₁₋₄ alkyl group, an aryl group, a heteroaryl group, aheterocyclic group, or an aralkyl group, and said alkyl group, arylgroup, heteroaryl group, heterocyclic group, and aralkyl group includingthose for R¹²⁶ and R¹²⁷ may have one to three substituents other thanhydrogen atom.
 24. The compound or the salt thereof, whereinR²²-N(R²⁴)-R²³ is represented byR^(101A)-R^(101B)CO-R^(101C)-R^(101D)-R^(101C)-COR^(101B)-R^(101A)wherein R^(101A) represents a C₁₋₄ lower alkylene group; R¹⁰¹Brepresents NH or methylene group; R^(101C) represents a single bond ormethylene group; R^(101D) represents a divalent bridging cyclichydrocarbon group, monocyclic hydrocarbon group, or heterocyclic group,and said bridging cyclic hydrocarbon group, monocyclic hydrocarbongroup, or heterocyclic group may have one to three substituents otherthan hydrogen atom.
 25. The compound or the salt thereof according toany one of claims 20 to 24, wherein Ar²³ and Ar²⁴ independentlyrepresent an aryl group which has, on its ring, one to three hydroxylgroups optionally substituted with a monovalent group and said arylgroup may have one to three substituents other than hydroxyl group onits ring.
 26. The compound or the salt thereof according to claim 25,wherein both of Ar²³ and Ar²⁴ are 4-hydroxyphenyl groups.
 27. Thecompound or the salt thereof according to any one of claims 20 to 26,wherein R²² and R²³ are the same groups, and the minimum number ofbridge-forming atoms of R²² and R²³ are from 1 to
 10. 28. The compoundor the salt thereof according to claim 27, wherein R²² and R²³ are thesame groups, and the minimum number of bridge-forming atoms of R²² andR²³ are from 1 to
 4. 29. The compound or the salt thereof according toany one of claims 20 to 28, wherein R²² and R²³ independently representmethylene group, ethylene group, propylene group or butylene group. 30.The compound or the salt thereof according to any one of claims 20 to28, wherein R²² and R²³ are the same groups, and represent methylenegroup, ethylene group, propylene group or butylene group.
 31. Thecompound or the salt thereof according to any one of claims 20 to 30,wherein the total number of carbon atoms is 35 or less.